Solid dispersion formulations and methods of use thereof

ABSTRACT

The present invention relates to formulations and methods for increasing the bioavailability of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one, 1-(3,3-diphenylpropanoyl)piperazine, or a salt thereof. In particular, the formulation can include one or more pharmaceutically acceptable matrix polymers to form a solid dispersion, e.g., a spray dried dispersion or a hot melt extrusion.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/414,369, filed on Mar. 7, 2012, which claims benefit of U.S.Provisional Application No. 61/450,479, filed on Mar. 8, 2011, and U.S.Provisional Application No. 61/485,405, filed on May 12, 2011, each ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to formulations and methods for increasingthe bioavailability of1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one or a metabolitethereof, as well as salts thereof. In particular, the formulations andmethods relate to the use of solid dispersions to improve meanbioavailability in fasted or fed subjects and/or to reduce food effect.

Ion channels mediate a variety of normal physiological functions and arealso implicated in a number of human disorders. Examples of humandisorders mediated by calcium channels include but are not limited tocongenital migraine, cerebellar ataxia, angina, epilepsy, hypertension,ischemia, and some arrhythmias (see, e.g., Janis et al., Ion CalciumChannels Their Properties, Functions, Regulation and Clinical Relevance(1991) CRC Press, London); and those mediated by sodium channels includebut are not limited to epilepsy, cancer, pain, migraine, Parkinson'sDisease, mood disorders, schizophrenia, psychosis, tinnitus, amyotrophiclateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessivecompulsive disorder, restless leg syndrome, and Tourette syndrome.Modulators of ion channels, e.g., such as1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one, a metabolitethereof, or a salt thereof, are thus desired. In particular,formulations of such modulators having improved oral bioavailabilityand/or reduced patient-to-patient variability in pharmacokineticbehavior are needed.

SUMMARY OF THE INVENTION

The invention provides formulations and methods for administering1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one (compound 1), ametabolite thereof (e.g., 1-(3,3-diphenylpropanoyl)piperazine (compound2)), or a salt thereof. Compound 1 is a potent N-type calcium channelantagonist having selectivity over other types of calcium channels(e.g., L-type or P/Q-type calcium channels). The invention also providesuse of these formulations for acting at ion channels (e.g., calciumchannels (e.g., N-type calcium channels) and/or sodium channels) and fortreating various conditions associated with these channels, such as painand epilepsy.

In a first aspect, the invention relates to a pharmaceutical compositionin unit dosage form for oral administration, the composition includingfrom about 20 mg to about 250 mg of substantially amorphous compound 1,compound 2, or a salt thereof, and a pharmaceutically acceptableexcipient (e.g., any described herein, such as one or morepharmaceutically acceptable matrix polymers described herein), where,following administration of the pharmaceutical composition to subjects,the ratio of the mean bioavailability for fed subjects to the meanbioavailability for fasted subjects is from about 1.0 to about 2.0.

In a second aspect, the invention relates to a pharmaceuticalcomposition in unit dosage form for oral administration, the compositionincluding from about 20 mg to about 250 mg (e.g., from 20 mg to 30 mg,from 20 mg to 40 mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20mg to 100 mg, from 20 mg to 125 mg, from 20 mg to 150 mg, from 20 mg to175 mg, from 20 mg to 200 mg, from 20 mg to 225 mg, from 30 mg to 40 mg,from 30 mg to 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30mg to 125 mg, from 30 mg to 150 mg, from 30 mg to 175 mg, from 30 mg to200 mg, from 30 mg to 225 mg, from 30 mg to 250 mg, from 40 mg to 50 mg,from 40 mg to 75 mg, from 40 mg to 100 mg, from 40 mg to 125 mg, from 40mg to 150 mg, from 40 mg to 175 mg, from 40 mg to 200 mg, from 40 mg to225 mg, from 40 mg to 250 mg, from 50 mg to 75 mg, from 50 mg to 100 mg,from 50 mg to 125 mg, from 50 mg to 150 mg, from 50 mg to 175 mg, from50 mg to 200 mg, from 50 mg to 225 mg, from 50 mg to 250 mg, from 60 mgto 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 150mg, from 60 mg to 175 mg, from 60 mg to 200 mg, from 60 mg to 225 mg,from 60 mg to 250 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg,from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mgto 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg,from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg)of substantially amorphous compound 1, compound 2, or a salt thereof, ina pharmaceutically acceptable matrix polymer. In some preferredembodiments, the unit dosage form comprises about 70 mg to about 250 mg(e.g., from 70 mg to 75 mg, from 70 mg to 100 mg, from 70 mg to 125 mg,from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to 200 mg, from70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100 mg, from 80 mgto 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg, from 80 mg to 200mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from 90 mg to 100 mg,from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mg to 175 mg, from90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250 mg, from 100 mgto 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg, from 100 mg to200 mg, from 100 mg to 225 mg, and from 100 mg to 250 mg) of compound 1,compound 2, or a salt thereof.

In some embodiments of any of the aspects herein, the percentage loadingof compound 1 or compound 2 is from about 1% to about 90% (w/w) (e.g.,from 1% to 19%, from 10% to 19%, from 10% to 20%, from 10% to 30%, from10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10%to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%,from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30%to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%,from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40% to 50%, from40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from 50%to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, 51% to 60%,from 51% to 70%, from 51% to 80%, from 51% to 90%, from 60% to 70%, from60% to 80%, from 60% to 90%, from 70% to 80%, and from 70% to 90%). Insome preferred embodiments, the percentage loading of compound 1 orcompound 2 is from about 10% to about 60% (w/w) (e.g., from 10% to 20%,from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 30%to 40%, from 30% to 50%, from 30% to 60%, from 40% to 50%, and from 40%to 60%).

In some embodiments, following administration of the pharmaceuticalcomposition to subjects (e.g., fed subjects or fasted subjects), themean bioavailability is greater than about 20% (e.g., greater than 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, oreven 99%) or between about 20% to about 90% (e.g., from 20% to 30%, from20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20%to 80%, from 20% to 90%, from 30% to 40%, from 30% to 50%, from 30% to60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 40% to 50%,from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 60%to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, from 70% to90%, and from 80% to 90%).

In some embodiments, the ratio of the mean bioavailability for fedsubjects to the mean bioavailability for fasted subjects is from about1.0 to about 2.0 (e.g., from 1.0 to 1.1, from 1.0 to 1.2, from 1.0 to1.3, from 1.0 to 1.4, from 1.0 to 1.5, from 1.0 to 1.6, from 1.0 to 1.7,from 1.0 to 1.8, from 1.0 to 1.9, from 1.3 to 1.4, from 1.3 to 1.5, from1.3 to 1.6, from 1.3 to 1.7, from 1.3 to 1.8, from 1.3 to 1.9, from 1.3to 2.0, from 1.5 to 1.6, from 1.5 to 1.7, from 1.5 to 1.8, from 1.5 to1.9, from 1.5 to 2.0, from 1.7 to 1.8, from 1.7 to 1.9, from 1.7 to 2.0,from 1.8 to 1.9, and from 1.8 to 2.0).

In some embodiments, administration of the pharmaceutical composition tofed and fasted subjects produces a coefficient of variation in C_(max)and/or AUC_(∞) of less than about 60% (e.g., less than 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, and 15%). In particular embodiments, thecoefficient of variation in C_(max) and/or AUC_(∞) is of from about 20%to about 60% (e.g., from 20% to 30%, from 20% to 35%, from 20% to 40%,from 20% to 45%, from 20% to 50%, from 20% to 55%, from 30% to 35%, from30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30%to 60%, from 35% to 40%, from 35% to 45%, from 35% to 50%, from 35% to55%, from 35% to 60%, from 40% to 45%, from 40% to 50%, from 40% to 55%,from 40% to 60%, from 45% to 50%, from 45% to 55%, from 45% to 60%, from50% to 55%, from 50% to 60%, and from 55% to 60%).

In some embodiments, administration of the pharmaceutical composition tofasted or fed subjects produces a coefficient of variation in C_(max)and/or AUC_(∞) of less than about 65% (e.g., less than 60%, 55%, 50%,45%, 40%, 35%, 30%, 25%, 20%, and 15%). In some embodiments,administration of the pharmaceutical composition to fasted or fedsubjects produces a coefficient of variation in C_(max) and/or AUC_(∞)of from about 30% to about 65% (e.g., from 30% to 35%, from 30% to 40%,from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from30% to 65%, from 35% to 40%, from 35% to 45%, from 35% to 50%, from 35%to 55%, from 35% to 60%, from 35% to 65%, from 40% to 45%, from 40% to50%, from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45% to 55%,from 45% to 60%, from 45% to 65%, from 50% to 55%, from 50% to 60%, from50% to 65%, from 55% to 60%, from 55% to 65%, and from 60% to 65%).

In some embodiments, administration of the pharmaceutical composition toa fasted subject produces a C_(max) that is greater than about 400 ng/mL(e.g., greater than about 450, 500, 550, 600, 650, 700, 750, or 800ng/mL and/or up to about 900, 1,000, or 1,500 ng/mL, e.g., from 400ng/mL to 1,500 ng/mL, from 400 ng/mL to 1,000 ng/mL, from 400 ng/mL to800 ng/mL, from 400 ng/mL to 700 ng/mL, from 500 ng/mL to 1,500 ng/mL,from 500 ng/mL to 1,000 ng/mL, from 500 ng/mL to 800 ng/mL, and from 500ng/mL to 700 ng/mL) and/or an AUC_(∞) that is greater than about 4,000hr*ng/mL (e.g., greater than 4,500, 5,000, 5,500, 6,000, 6,500, 7,000,7,500, or 8,000 hr*ng/mL and/or up to 8,000 hr*ng/mL, e.g., from 4,000hr*ng/mL to 8,000 hr*ng/mL, from 4,500 hr*ng/mL to 8,000 hr*ng/mL, from5,000 hr*ng/mL to 8,000 hr*ng/mL, from 4,000 hr*ng/mL to 7,000 hr*ng/mL,from 4,500 hr*ng/mL to 7,000 hr*ng/mL, and from 5,000 hr*ng/mL to 7,000hr*ng/mL) for a 225 mg dose of compound 1 or compound 2.

In any of the above aspects, the pharmaceutical composition includes asolid dispersion of the compound 1, compound 2, or the salt thereof, anda pharmaceutically acceptable matrix polymer, where the weight ratio ofthe compound 1, compound 2, or the salt thereof, to the pharmaceuticallyacceptable matrix polymer is from about 1:6 to about 1:1.5 (e.g., from1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to 1:3.5, from1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to 1:2, from1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to 1:4, from1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4 to 1:2,from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3 to1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5, and from 1:2 to 1:1.5).

In some embodiments, at least about 90% (e.g., at least 95%, 96%, 97%,98%, 99%, 99.5%, or even 99.9%, such as from 90% to 99.9%, from 90% to99.5%, from 90% to 99%, from 90% to 98%, from 90% to 97%, from 90% to96%, from 90% to 95%, from 95% to 99.9%, from 95% to 99.5%, from 95% to99%, from 95% to 98%, from 95% to 97%, and from 95% to 96%) of thecompound 1, compound 2, or the salt thereof, is in amorphous form.

In some embodiments, the pharmaceutically acceptable matrix polymerincludes a polymer selected from a cellulose derivative, a polyacrylate,a polyvinyl pyrrolidone, a polyvinyl acetate, or a copolymer of apolyvinyl pyrrolidone and a polyvinyl acetate.

In further embodiments, the cellulose derivative is a cellulose acetatehaving from about 10% to about 50% (e.g., from 10% to 15%, from 10% to20%, from 10% to 25%, from 10% to 30%, from 10% to 35%, from 10% to 40%,from 10% to 45%, from 20% to 25%, from 20% to 30%, from 20% to 35%, from20% to 40%, from 20% to 45%, from 20% to 50%, from 25% to 30%, from 25%to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 30% to35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 35% to 40%,from 35% to 45%, from 35% to 50%, from 40% to 45%, and from 40% to 50%)acetyl. In further embodiments, the cellulose acetate is celluloseacetate phthalate (CAP) (e.g., having about 35% phthalyl/24% acetyl),methylcellulose acetate phthalate, hydroxypropylmethyl celluloseacetate, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS)(e.g., having about 9% acetyl/11% succinoyl, 12% acetyl/6% succinoyl,and 8% acetyl/15% succinoyl).

In some embodiments, the mean particle size of the matrix polymer isabout 1 mm or about 5 μm. In particular embodiments, the matrix polymeris HPMCAS having a mean particle size of about 1 mm (e.g., grade MG) orabout 5 μm (e.g., grade MF).

In other embodiments, the cellulose derivative is selected from an alkylcellulose (e.g., methyl cellulose and ethyl cellulose), a hydroxyalkylcellulose (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, such as those having 11% hydroxypropyl or 8%hydroxypropyl, and hydroxybutyl cellulose), a hydroxyalkylalkylcellulose (e.g., hydroxyethylmethyl cellulose and hydroxypropylmethylcellulose (HPMC) having 19-24% methoxyl/7-12% hydroxypropxyl, 28-30%methoxyl/7-12% hydroxypropxyl, 23% methoxyl/10% hydroxypropxyl, 23%-29%methoxyl/8%-9% hydroxypropxyl, 29% methoxyl/9% hydroxypropxyl, and 23%methoxyl/6% hydroxypropxyl), a hydroxyalkylalkyl cellulose ester (e.g.,hydroxypropylmethyl cellulose phthalate (HPMCP)), a carboxyalkylcellulose (e.g., carboxymethyl cellulose and alkali metal salts thereof,such as sodium salts), a carboxyalkylalkyl cellulose (e.g.,carboxymethylethyl cellulose), and a carboxyalkyl cellulose ester (e.g.,carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate,carboxymethyl cellulose acetate butyrate, and carboxymethyl celluloseacetate propionate). In further embodiment, the cellulose derivative isfurther cross-linked or copolymerized (e.g., with any matrix polymerdescribed herein).

In some embodiments, the matrix polymer is the polyacrylate selectedfrom a polymethacrylate, a methacrylate copolymer (e.g., a methacrylicacid-methyl methacrylate copolymer having a 1:1 ratio of free carboxylgroups to ester groups and a 1:2 ratio of free carboxyl groups to estergroups, a dimethylaminoethyl methacrylate-butyl methacrylate-methylmethacrylate copolymer, and a diethylaminoethyl methacrylic acid-methylmethacrylate copolymer), and an ethacrylate copolymer (e.g., amethacrylic acid ethacrylate copolymer having a 50:50 ratio ofmethacrylic acid to ethacrylate).

In some embodiments, the matrix polymer is the polyvinyl acetateselected from a polyvinyl pyrrolidone (e.g., povidone) having amolecular weight more than about 2,000 (e.g., about 2,500, about 9,000,about 50,000, and about 1,250,000), a polyvinyl acetate ester (e.g.,polyvinyl acetate phthalate (PVAP)), and a polyethylene glycolpolyvinylacetate copolymer (e.g., polyethyleneglycol-polyvinylcaprolactam-polyvinylacetate copolymer).

In other embodiments, the matrix polymer is the copolymer of a polyvinylpyrrolidone and a polyvinyl acetate and the copolymer has from about10:90 to about 70:30 ratio (e.g., 20:80, 30:70, 40:60, 50:50, and 60:40)of N-vinyl-2-pyrrolidone to vinyl acetate.

In some embodiments, the pharmaceutical composition further includes aplasticizer. Exemplary plasticizers include those selected from apolyalkylene oxide (e.g., polyethylene glycols, such as PEG 300, PEG400, PEG 4000, and PEG 8000, and polypropylene glycols), a copolymer ofethylene oxide and propylene oxide (e.g., ethoxylated propoxylated blockcopolymers having the formulaH(OCH₂CH₂)_(a)(OCHCH₃CH₂)_(b)(OCH₂CH₂)_(a)OH, where a is between 10 and150 and b is between 10 and 100 (e.g., where a is about 12 and b isabout 20, a is about 38 and b is about 29, a is about 80 and b is about27, a is about 64 and b is about 37, a is about 141 and b is about 44, ais about 49 and b is about 57, and a is about 101 and b is about 56),and a polyethoxylated glyceryl ester (e.g., polyoxyl 35 castor oil andpolyoxyl 40 castor oil having 40-45 moles of ethylene oxide).

In some embodiments, the composition further includes a surfactant.Exemplary surfactants include those selected from a polyethoxylatedester of one or more fatty acids, a polyethoxylated alkyl ether, apolyethoxylated glyceryl ester, a polyoxyethylene glyceryl ester of oneor more fatty acids, a sorbitan ester, a polyethoxylated sorbitan ester,a polyethoxylated vitamin analog (e.g., a pegylated vitamin E compound,e.g., D-alpha-tocopheryl PEG 1000 succinate), and an ethoxylatedpropoxylated block copolymer.

In other embodiments, the solid dispersion is formed by spray drying aliquid mixture including compound 1, compound 2, or the salt thereof,and the pharmaceutically acceptable matrix polymer. In some embodiments,the matrix polymer is a cellulose derivative (e.g., any describedherein).

In some embodiments, the solid dispersion is formed by hot meltextrusion of a mixture including compound 1, compound 2, or the saltthereof, and the pharmaceutically acceptable matrix polymer. In someembodiments, the matrix polymer is a cellulose derivative (e.g.,hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulosephthalate (HPMCP), cellulose acetate phthalate (CAP),hydroxypropylmethyl cellulose acetate succinate (HPMCAS), or anydescribed herein), a polyacrylate (e.g., a polymethacrylate, amethacrylate copolymer, or any described herein, e.g., a methacrylicacid-methyl methacrylate copolymer (e.g., Eudragit® L 100 or Eudragit® S100, MW ˜125,000 g/mol), a dimethylaminoethyl methacrylate-butylmethacrylate-methyl methacrylate copolymer (e.g., Eudragit® E PO,Eudragit® E 100, or Eudragit® E 12.5, respectively), a diethylaminoethylmethacrylic acid-methyl methacrylate copolymer (e.g., Eudragit® E), oran ethacrylate copolymer, such as a methacrylic acid ethacrylatecopolymer (e.g., Kollicoat® MAE 100P or Eudragit®L 100-55), a polyvinylpyrrolidone, a polyvinyl acetate, or a copolymer of a polyvinylpyrrolidone and a polyvinyl acetate.

In a third aspect, the invention features a method for reducing the foodeffect exhibited by compound 1, compound 2, or a salt thereof, followingadministration to a subject, the method including administering a unitdosage form including any pharmaceutical composition described herein tothe subject.

In a fourth aspect, the invention features a method to treat a diseaseor condition (e.g., pain, epilepsy, or any described herein), the methodincluding administering to a subject (e.g., a fasted subject or a fedsubject) in need of such treatment an effective amount of anypharmaceutical composition described herein.

In a fifth aspect, the invention features a method to treat a disease orcondition (e.g., pain, epilepsy, or any described herein) modulated byion channel activity, the method including administering to a subject(e.g., a fasted subject or a fed subject) in need of such treatment aneffective amount of any pharmaceutical composition described herein.

In a sixth aspect, the invention features a method of inhibiting an ionchannel, the method including contacting a cell (e.g., a cell from afasted subject or a cell from a fed subject) with any pharmaceuticalcomposition described herein (e.g., an effective amount of anypharmaceutical composition described herein).

In some embodiments of the above aspects, the ion channel is a calciumchannel or a sodium channel. In some embodiments, the calcium channel isan N-type calcium channel (e.g., the Ca_(V) 2.2 channel). In someembodiments, the sodium channel is a voltage-gated sodium channel (e.g.,the Na_(V)1.7 channel or the Na_(V)1.8, channel).

In some embodiments, the condition is pain, epilepsy, Parkinson'sdisease, a mood disorder (e.g., a major depressive disorder (e.g.,atypical depression, melancholic depression, psychotic major depression,catatonic depression, postpartum depression, seasonal affectivedisorder, dysthymia, and depressive disorder not otherwise specified(DD-NOS)), recurrent brief depression, minor depressive disorder, or abipolar disorder), psychosis (e.g., schizophrenia), tinnitus,amyotrophic lateral sclerosis, glaucoma, ischaemia, a spasticitydisorder, obsessive compulsive disorder, restless leg syndrome, orTourette syndrome. In particular embodiments, the condition is pain orepilepsy.

In some embodiments, the pain is inflammatory pain (e.g., caused byrheumatoid arthritis, juvenile idiopathic arthritis, ankylosingspondylitis, psoriatic arthritis, inflammatory bowel disease, primarydysmenorrhea, or endometriosis) or neuropathic pain. In otherembodiments, the pain is chronic pain. In further embodiments, thechronic pain is peripheral neuropathic pain (e.g., post-herpeticneuralgia, diabetic neuropathic pain, neuropathic cancer pain,HIV-associated neuropathy, erythromelalgia, failed back-surgerysyndrome, trigeminal neuralgia, or phantom limb pain), centralneuropathic pain (e.g., multiple sclerosis related pain, Parkinsondisease related pain, post-stroke pain, post-traumatic spinal cordinjury pain, lumbosacral radiculopathy, cervical radiculopathy, brachialradiculopathy, or pain in dementia), musculoskeletal pain (e.g.,osteoarthritic pain or fibromyalgia syndrome), headache (e.g., migraine,cluster headache, tension headache syndrome, facial pain, or headachecaused by other diseases), visceral pain (e.g., interstitial cystitis,irritable bowel syndrome, or chronic pelvic pain syndrome), or mixedpain (e.g., lower back pain, neck and shoulder pain, burning mouthsyndrome, or complex regional pain syndrome). In still otherembodiments, the pain is acute pain. In further embodiments, the acutepain is nociceptive pain or post-operative pain.

In a seventh aspect, the invention features a method of preparing anypharmaceutical composition described herein, the method includingpreparing a mixture (e.g., a liquid mixture) or a solution includingcompound 1, compound 2, or a salt thereof, and a pharmaceuticallyacceptable matrix polymer; and spray drying the mixture or the solutionto form a solid dispersion (e.g., a spray dried dispersion).

In an eighth aspect, the invention features a method of preparing anypharmaceutical composition described herein, the method includingpreparing a mixture or a solution including compound 1, compound 2, or asalt thereof, and a pharmaceutically acceptable matrix polymer; heating(e.g., up to or above the transition glass temperature or meltingtemperature of the matrix polymer) the mixture to form a homogenousmolten mass; extruding the molten mass; and cooling the molten mass toform a solid dispersion (e.g., a hot melt extrusion).

In some embodiments of the seventh and eighth aspects, the mixture orthe solution further includes a solvent (e.g., one or more of dimethylacetamide, dimethyl formamide, pyrrolidone, methylpyrrolidone, methanol,ethanol, and acetone).

In some embodiments, the mixture or the solution further includes apharmaceutically acceptable excipient (e.g., butylated hydroxytoluene(BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate,croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid,crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,maltitol, mannitol, methionine, methylcellulose, methyl paraben,microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone,povidone, pregelatinized starch, propyl paraben, retinyl palmitate,shellac, silicon dioxide, sodium carboxymethyl cellulose, sodiumcitrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid,stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E,vitamin C, and xylitol). Further exemplary excipients include an inertdiluent or filler (e.g., sucrose, sorbitol, sugar, mannitol,microcrystalline cellulose, a starch including potato starch, kaolin,calcium carbonate, sodium chloride, lactose, such as lactosemonohydrate, calcium phosphate, calcium sulfate, and sodium phosphate);a granulating agent or a disintegrating agent (disintegrant) (e.g., acellulose derivative including microcrystalline cellulose, a starchincluding potato starch and sodium starch glycolate, croscarmellosesodium, alginate, and alginic acid); a binding agent (e.g., sucrose,glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin,starch, pregelatinized starch, microcrystalline cellulose, lactose, suchas lactose monohydrate, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, and polyethyleneglycol); a lubricant (e.g., magnesium stearate, calcium stearate, zincstearate, sodium stearyl fumurate, sodium lauryl sulfate, stearic acid,hydrogenated vegetable oil, mineral oil, PEG 4000-6000, sodium benzoate,glyceryl palmitostearate, glyceryl behenate, and talc); a wetting agentor a surfactant (e.g., sodium lauryl sulfate, polysorbate 80, and apegylated vitamin E compound, as described herein); a glidant (e.g.,magnesium stearate, calcium stearate, zinc stearate, colloidal silicondioxide, magnesium carbonate, silica, such as fumed silica, and talc);an antiadhesive (e.g., magnesium stearate, calcium stearate, zincstearate, fumed silica, and talc); a colorant; a flavoring agent; aplasticizer; a humectant; a buffering agent; an antioxidant; a coatingor a film former; a compression aid; an emollient; an emulsifier; afragrance; a preservative; a printing ink; a sorbent; a suspensing ordispersing agent; a sweetener; and waters of hydration.

In some embodiments, the composition includes of from about 1% to about30% (w/w) of compound 1, compound 2, or a salt thereof (e.g., at anyuseful weight percentage range, as described herein). In furtherembodiments, the composition further includes of from about 25% to about85% (w/w) of one or more pharmaceutically acceptable matrix polymers(e.g., from 25% to 50%, from 25% to 60%, from 25% to 70%, from 25% to80%, from 35% to 50%, from 35% to 60%, from 35% to 70%, from 35% to 80%,from 35% to 85%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from50% to 85%, from 60% to 70%, from 60% to 80%, from 60% to 85%, from 70%to 80%, and from 70% to 85%); from about 15% to about 40% (w/w) of oneor more binding agents; from about 1% to about 5% (w/w) of one or moredisintegrating agents; from about 0.1% to about 2% (w/w) of one or morewetting agents; from about 0.1% to about 1% (w/w) of a glidant; and fromabout 0.1% to about 1% (w/w) of a lubricant. In particular embodiments,the composition further included of from about 1% to about 5% (w/w) ofone or more surfactants (e.g., vitamin E TPGS).

In further embodiments of the seventh and eighth aspects, the methodfurther includes filling the unit dosage form with the solid dispersion.

In some embodiments, the matrix polymer is selected from the groupconsisting of a cellulose derivative (e.g., a cellulose acetate havingfrom about 10% to about 50% acetyl, an alkyl cellulose, a hydroxyalkylcellulose, a hydroxyalkylalkyl cellulose, a hydroxyalkylalkyl celluloseester, a carboxyalkyl cellulose, a carboxyalkylalkyl cellulose, and acarboxyalkyl cellulose ester, or any described herein), a polyacrylate(e.g., a polymethacrylate, a methacrylate copolymer, and an ethacrylatecopolymer, or any described herein), a polyvinyl pyrrolidone (e.g.,povidone, copovidone, or any described herein), a polyvinyl acetate(e.g., polyvinyl acetate ester, such as polyvinylacetate phthalate(PVAP), and a polyethylene glycol-polyvinylcaprolactam-polyvinylacetatecopolymer, or any described herein), or a copolymer of a polyvinylpyrrolidone and a polyvinyl acetate (e.g., having from 10:90 to 70:30ratio of N-vinyl-2-pyrrolidone to vinyl acetate). In some embodiments,the cellulose acetate is selected from cellulose acetate phthalate(CAP), methylcellulose acetate phthalate, hydroxypropylmethyl celluloseacetate, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

In some embodiments, the mixture or the solution further includes aplasticizer selected from a polyalkylene oxide (e.g., polyethyleneglycols, such as PEG 300, PEG 400, and PEG 8000, and polypropyleneglycols), a copolymer of ethylene oxide and propylene oxide (e.g.,ethoxylated propoxylated block copolymers having the formulaH(OCH₂CH₂)_(a)(OCHCH₃CH₂)_(b)(OCH₂CH₂)_(a)OH, where a is about 38 and bis about 29 and where a is about 49 and b is about 57), and apolyethoxylated glyceryl ester (e.g., polyoxyl 35 castor oil andpolyoxyl 40 castor oil having 40-45 moles of ethylene oxide).

In any of the aspects described herein, the composition includescompound 1 or a salt thereof.

In any of the aspects described herein, the composition includescompound 2 or a salt thereof.

In any of the aspects described herein, the composition includes HPMCAS.

In any of the above aspects, the unit dosage form includes from about 20mg to about 100 mg (e.g., about 75 mg) of compound 1, compound 2, or asalt thereof.

In any of the above aspects, the compound 1, compound 2, or the saltthereof, is the hydrochloride salt of compound 1, the hydrochloride saltof compound 2, the free base form of compound 1, or the free base formof compound 2.

In any of the above aspects, the compound 1 is the free base form ofcompound 1.

In any of the above aspects, the unit dosage form is a tablet, hardgelatin capsule, a hard hydroxypropyl methylcellulose capsule, or a softgelatin capsule.

In any of the above aspects, the unit dosage form includes from about 20mg to about 250 mg of compound 1, compound 2, or a salt thereof, such asfrom 20 mg to 30 mg, from 20 mg to 40 mg, from 20 mg to 50 mg, from 20mg to 75 mg, from 20 mg to 100 mg, from 20 mg to 125 mg, from 20 mg to150 mg, from 20 mg to 175 mg, from 20 mg to 200 mg, from 20 mg to 225mg, from 30 mg to 40 mg, from 30 mg to 50 mg, from 30 mg to 75 mg, from30 mg to 100 mg, from 30 mg to 125 mg, from 30 mg to 150 mg, from 30 mgto 175 mg, from 30 mg to 200 mg, from 30 mg to 225 mg, from 30 mg to 250mg, from 40 mg to 50 mg, from 40 mg to 75 mg, from 40 mg to 100 mg, from40 mg to 125 mg, from 40 mg to 150 mg, from 40 mg to 175 mg, from 40 mgto 200 mg, from 40 mg to 225 mg, from 40 mg to 250 mg, from 50 mg to 75mg, from 50 mg to 100 mg, from 50 mg to 125 mg, from 50 mg to 150 mg,from 50 mg to 175 mg, from 50 mg to 200 mg, from 50 mg to 225 mg, from50 mg to 250 mg, from 60 mg to 75 mg, from 60 mg to 100 mg, from 60 mgto 125 mg, from 60 mg to 150 mg, from 60 mg to 175 mg, from 60 mg to 200mg, from 60 mg to 225 mg, from 60 mg to 250 mg, from 70 mg to 75 mg,from 70 mg to 100 mg, from 70 mg to 125 mg, from 70 mg to 150 mg, from70 mg to 175 mg, from 70 mg to 200 mg, from 70 mg to 225 mg, from 70 mgto 250 mg, from 80 mg to 100 mg, from 80 mg to 125 mg, from 80 mg to 150mg, from 80 mg to 175 mg, from 80 mg to 200 mg, from 80 mg to 225 mg,from 80 mg to 250 mg, from 90 mg to 100 mg, from 90 mg to 125 mg, from90 mg to 150 mg, from 90 mg to 175 mg, from 90 mg to 200 mg, from 90 mgto 225 mg, from 90 mg to 250 mg, from 100 mg to 125 mg, from 100 mg to150 mg, from 100 mg to 175 mg, from 100 mg to 200 mg, from 100 mg to 225mg, and from 100 mg to 250 mg.

In any of the above aspects, the unit dosage form is administered toachieve a daily amount of from about 25 mg to about 1,600 mg (e.g., from40 mg to 1,600 mg, from 40 mg to 1,000 mg, from 40 mg to 800 mg, from 40mg to 700 mg, from 40 mg to 600 mg, from 40 mg to 500 mg, from 40 mg to400 mg, from 40 mg to 300 mg, from 40 mg to 200 mg, from 50 mg to 1,600mg, from 50 mg to 1,000 mg, from 50 mg to 800 mg, from 50 mg to 700 mg,from 50 mg to 600 mg, from 50 mg to 500 mg, from 50 mg to 400 mg, from50 mg to 300 mg, from 50 mg to 200 mg, from 60 mg to 1,600 mg, from 60mg to 1,000 mg, from 60 mg to 800 mg, from 60 mg to 700 mg, from 60 mgto 600 mg, from 60 mg to 500 mg, from 60 mg to 400 mg, from 60 mg to 300mg, from 60 mg to 200 mg, from 80 mg to 1,600 mg, from 80 mg to 1,000mg, from 80 mg to 800 mg, from 80 mg to 700 mg, from 80 mg to 600 mg,from 80 mg to 500 mg, from 80 mg to 400 mg, from 80 mg to 300 mg, from80 mg to 200 mg, from 100 mg to 1,600 mg, from 100 mg to 1,000 mg, from100 mg to 800 mg, from 100 mg to 700 mg, from 100 mg to 600 mg, from 100mg to 500 mg, from 100 mg to 400 mg, from 100 mg to 300 mg, from 100 mgto 200 mg, from 150 mg to 1,600 mg, from 150 mg to 1,000 mg, from 150 mgto 800 mg, from 150 mg to 700 mg, from 150 mg to 600 mg, from 150 mg to500 mg, from 150 mg to 400 mg, from 150 mg to 300 mg, and from 150 mg to200 mg, such as from 40 mg to 800 mg and from 80 mg to 320 mg) ofcompound 1, compound 2, or a salt thereof. In additional aspects, theunit dosage form is administered to achieve a daily amount of up to1,600 mg (e.g., up to 1,500 mg, up to 1,250 mg, up to 1,000 mg, up to750 mg, up to 500 mg, up to 450 mg, up to 400 mg, up to 350 mg, up to300 mg, up to 250 mg, up to 200 mg, up to 150 mg, up to 100 mg, and upto 50 mg, preferably up to 400 mg) or a daily amount of from about 50 mgto about 1,600 mg (e.g., from 150 mg to 200 mg, from 150 mg to 225 mg,from 150 mg to 500 mg, from 150 mg to 750 mg, from 150 mg to 900 mg,from 150 mg to 1,000 mg, from 150 mg to 1,250 mg, from 150 mg to 1,500mg, from 150 mg to 1,600 mg, from 200 mg to 225 mg, from 200 mg to 500mg, from 200 mg to 750 mg, from 200 mg to 900 mg, from 200 mg to 1,000mg, from 200 mg to 1,250 mg, from 200 mg to 1,500 mg, from 200 mg to1,600 mg, from 225 mg to 500 mg, from 225 mg to 750 mg, from 225 mg to900 mg, from 225 mg to 1,000 mg, from 225 mg to 1,250 mg, from 225 mg to1,500 mg, from 225 mg to 1,600 mg, from 500 mg to 750 mg, from 500 mg to900 mg, from 500 mg to 1,000 mg, from 500 mg to 1,250 mg, from 500 mg to1,500 mg, from 500 mg to 1,600 mg, from 750 mg to 900 mg, from 750 mg to1,000 mg, from 750 mg to 1,250 mg, from 750 mg to 1,500 mg, from 750 mgto 1,600 mg, from 900 mg to 1,000 mg, from 900 mg to 1,250 mg, from 900mg to 1,500 mg, from 900 mg to 1,600 mg, from 1,000 mg to 1,250 mg, from1,000 mg to 1,500 mg, from 1,000 mg to 1,600 mg, from 1,250 mg to 1,500mg, from 1,250 mg to 1,600 mg, and from 1,500 mg to 1,600 mg, e.g.,about 225 mg) of compound 1, compound 2, or a salt thereof. In furtheraspects, the unit dosage form is administered one to five times daily(e.g., one, two, three, four, or five times daily).

DEFINITIONS

By “pharmaceutically acceptable excipient” is meant any ingredient otherthan the active ingredient and capable of maintaining the activeingredient in a substantially amorphous form.

By “pharmaceutically acceptable matrix polymer” is meant a polymersuitable for pharmaceutical formulation and capable of forming a soliddispersion.

As used herein, the term “substantially amorphous” refers to a soliddosage form containing compound 1, compound 2, or a salt thereof, inwhich less than 20% (w/w) of the compound 1, compound 2, or a saltthereof, is present in a crystalline form (e.g., less than 15%, 12%,10%, 8%, 5%, 3%, or 1% (w/w) is present in a crystalline form, such asbetween 0.01% and 20%, 0.01% and 15%, 0.01% and 12%, 0.01% and 10%,0.01% and 8%, 0.01% and 5%, 0.01% and 3%, and 0.01% and 1% (w/w) incrystalline form). The crystalline content of a solid dosage form can beassessed using x-ray diffraction techniques.

As used herein, the term “solid dispersion” encompasses systems havingsubstantially amorphous active ingredient dispersed in a matrix polymer.In certain dosage forms of the invention, the solid dispersion is a formhaving homogenously dispersed active ingredient throughout the matrixpolymer in a manner that results in a single glass transitiontemperature T_(g).

As used herein, “about” means +/−10% of the recited value.

As used herein, “bioavailability” refers to the fraction of drugabsorbed following administration to a subject or patient under a fastedstate. Under fasted states, the bioavailability of compound 1, compound2, or a salt thereof, formulated as described herein is at least about15%, but may be greater than 20%, 25%, 30%, 35%, 40%, 45%, or 50% of thedose administered.

By “coefficient of variation” is meant the arithmetic standard deviationdivided by the arithmetic mean for a particular pharmacokineticparameter, where the data is obtained from a pharmacokinetic studyinvolving 10, 12, or more subjects or patients.

By “mean” is meant the arithmetic mean for a particular pharmacokineticparameter, where the data is obtained from a pharmacokinetic studyinvolving 10, 12, or more subjects or patients.

By “C_(max)” is meant the mean peak concentration of a drug achieved inplasma after dosing.

By “T_(max)” is meant the mean time after oral administration of a drugwhen the maximum plasma concentration of the drug or C_(max) is reached.

By “AUC_(∞),” “AUC_(0-∞),” or “Area Under the Curve_(∞)” is meant themean integrated area under the curve for the plasma concentration of adrug, versus time from t=0 to ∞ following dosing.

By “food effect” is meant is meant a difference between any one or moreof C_(max), T_(max), AUC_(∞), and bioavailability for a drug,administered under fasted states in comparison to the drug administeredunder fed states.

As used herein, “reducing the food effect” refers to narrowing thedifference between any one of C_(max), T_(max), AUC_(∞), andbioavailability for a drug administered under fasted states incomparison to the drug administered under fed states.

By “fasted” or “fasted states” is meant a subject has not eaten for atleast about four hours prior and about four hours subsequent to drugadministration.

By “fed” or “fed states” is meant a subject has eaten within about 30minutes prior to drug administration. The meal can be a fatty meal, andthe resulting mean pharmacokinetic parameters can be characteristic ofconsuming a fatty meal. For example, the “fed state” can be a human whohas eaten a United States Food and Drug Administration (FDA) standardhigh fat breakfast (or another meal containing a comparable quantity offat and calories) within 30 minutes prior to drug administration. Atypical FDA standard breakfast consists of 2 eggs fried in butter, 2strips of bacon, 2 slices of toast with butter, 4 ounces of hash brownpotatoes, and 8 ounces of whole milk. The meal is high in both fat(approximately 50% of total calorie content of the meal) and calories(approximately 800-1,000 calories).

By “pegylated vitamin E compound” is meant a compound or mixture ofcompounds containing one or more vitamin E moieties (e.g., a tocopherol,tocomonoenol, tocodienol, or tocotrienol) bonded to (e.g., by an ester,amide, or thioester bond) to one or more polyethylene glycol (PEG)moieties via a linker (e.g., a dicarboxylic or tricarboxylic acid). Thevitamin E moiety can be any naturally occurring or synthetic form ofvitamin E, including α-, β-, γ-, and δ-isoforms, and all stereoisomersof tocopherol, tocomonoenol, tocodienol, and tocotrienol. Linkersinclude, for example, dicarboxylic acids (e.g., succinic acid, sebacicacid, dodecanedioic acid, suberic acid, or azelaic acid, citraconicacid, methylcitraconic acid, itaconic acid, maleic acid, glutaric acid,glutaconic acid, fumaric acids, and phthalic acids). Exemplarytocopherol polyethylene glycol diesters are D-alpha-tocopheryl PEGsuccinate, tocopherol sebacate polyethylene glycol, tocopheroldodecanodioate polyethylene glycol, tocopherol suberate polyethyleneglycol, tocopherol azelaate polyethylene glycol, tocopherol citraconatepolyethylene glycol, tocopherol methylcitraconate polyethylene glycol,tocopherol itaconate polyethylene glycol, tocopherol maleatepolyethylene glycol, tocopherol glutarate polyethylene glycol,tocopherol glutaconate polyethylene glycol, and tocopherol phthalatepolyethylene glycol. Each of the PEG moieties of the pegylated vitamin Ecompound can be any polyethylene glycol or any PEG derivative, and canhave a molecular weight of 200-6,000 kDa (e.g., 400-4,000 kDa, 500-2,000kDa, 750-1,500 kDa, 800-1,200 kDa, 900-1,100 kDa, or about 1,000 kDa).The PEG moieties can be polydisperse; that is, they can have a varietyof molecular weights. PEG derivatives include, for example, methylatedPEG, propylene glycol, PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H,PEG-OMe and other ethers, branched PEGs, and PEG copolymers (e.g.,PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, andPPG-PEG-PPG-2000). Any known source of pegylated vitamin E compound canbe used in the present invention. An exemplary pegylated vitamin Ecompound is tocopheryl PEG-1000 succinate (TPGS-1000), which has a PEGmoiety having a molecular weight of 1,000 kDa. A food grade TPGS-1000 isavailable, for example, under the trade name Eastman Vitamin E TPGS®(Eastman Chemical Company, Kingsport, Tenn.). This TPGS is water-solubleform of natural-source vitamin E, which is prepared by esterification ofcrystalline D-α-tocopheryl acid succinate with polyethylene glycol 1000(PEG 1000), and contains between 260 and 300 mg/g total tocopherol.Another exemplary pegylated vitamin E compound is Water Soluble NaturalVitamin E (ZMC-USA, The Woodlands, Tex.). Methods of preparing pegylatedvitamin E are described in U.S. Pat. Nos. 2,680,749 and 3,102,078 and inU.S. Publication Nos. 2007/0184117 and 2007/0141203, which are hereinincorporated by reference. Pegylated vitamin E compounds also includeanalogs that differ in chemical composition from tocopheryl PEGsuccinate (e.g., TPGS-1000) by the substitution, addition, or removal ofone or more atoms, methylene (CH₂)_(n) units, or functional groups.Pegylated vitamin E compounds also include chromanol derivatives (e.g.,6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate),steroid derivatives (e.g., cholesteryl PEG-1000 succinate, cholic acidPEG-1000, dihydro cholic acid PEG-1000, litho-cholic acid PEG-1000,ursodeoxycholic acid PEG-1000, chenodeoxycholic acid PEG-1000), andothers (e.g., indomethacin PEG-1000, chromone-2-carboxylic acidPEG-1000, chromone-2-carboxylic acid PEG-1100-OMe, chromone-2-carboxylicacid PEG-1500, chromone-2-carboxylic acid PEG-2000, naproxen PEG-1000,probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000,5-(4-chlorophenyl)-2-furoic acid PEG-1000, probenecid tocopherylPEG-1000 succinate, lithocholic acid PEG-1000, and chromone-3-carboxylicacid PEG-1000, 7-hydroxy-coumarinyl-4-acetic acid PEG-1000).

The term “unit dosage form” refers to a physically discrete unitsuitable as a unitary dosage, such as a tablet, caplet, hard capsule, orsoft capsule, each unit containing a predetermined quantity of a drug.

As used herein, the term “administration” or “administering” refers toperoral (e.g., oral) administration of a drug to a subject or patient.

By “effective” amount is meant the amount of a drug sufficient to treat,prevent, or ameliorate a condition in a subject or patient. Theeffective amount of compound 1, compound 2, or salt thereof, used topractice the present invention for therapeutic management of a conditionvaries depending upon one or more of the manner of administration, theage, body weight, sex, and/or general health or malady of the patient.The prescribers will primarily decide the appropriate amount and dosageregimen. Such amount is referred to as an “effective” amount.

As used herein, and as well understood in the art, “to treat” acondition or “treatment” of the condition (e.g., the conditionsdescribed herein such as pain (e.g., chronic or acute pain), epilepsy,Alzheimer's disease, Parkinson's disease, cardiovascular disease,diabetes, cancer, sleep disorders, obesity, mood disorders, psychosissuch as schizophrenia, tinnitus, amyotrophic lateral sclerosis,glaucoma, ischaemia, spasticity disorders, obsessive compulsivedisorder, restless leg syndrome, Tourette syndrome, overactive bladder,renal disease, neuroprotection, addiction, or male birth control) is anapproach for obtaining beneficial or desired results, such as clinicalresults. Beneficial or desired results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions;diminishment of extent of disease, disorder, or condition; stabilized(i.e., not worsening) state of disease, disorder, or condition;preventing spread of disease, disorder, or condition; delay or slowingthe progress of the disease, disorder, or condition; amelioration orpalliation of the disease, disorder, or condition; and remission(whether partial or total), whether detectable or undetectable.“Palliating” a disease, disorder, or condition means that the extentand/or undesirable clinical manifestations of the disease, disorder, orcondition are lessened and/or time course of the progression is slowedor lengthened, as compared to the extent or time course in the absenceof treatment.

Other features and advantages of the invention will be apparent from thefollowing detailed description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1H are graphs showing the dissolution rate in gastric media forsolid dispersion formulations having 20% (w/w) loading of compound 1 anda gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. Thefollowing solid dispersion formulations were tested: carboxymethylethylcellulose (CMEC, FIG. 1A), cellulose acetate phthalate (CAP, FIG. 1B),hydroxypropylmethyl cellulose acetate succinate M grade (HPMCAS-M, FIG.1C), polyvinyl acetate phthalate (PVAP, FIG. 1D), methacrylicacid-methyl methacrylate copolymer (Eudragit® L 100, FIG. 1E),polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer(Soluplus®, FIG. 1F), hydroxypropylmethyl cellulose phthalate(HPMCP-H55, FIG. 1G), and polyvinylpyrrolidone vinylacetate copolymer(PVP-VA, FIG. 1H). The total drug species are represented by opencircles with error bars, and the free drug species are represented byclosed circles with error bars. The solubility of unformulated compound1 in the gastric and FaSSIF media is shown in FIG. 1A.

FIGS. 2A-2C are graphs showing the dissolution rate in gastric media forsolid dispersion formulations having 35% (w/w) loading of compound 1 anda gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. Thefollowing solid dispersion formulations were tested: cellulose acetatephthalate (CAP, FIG. 2A), hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M, FIG. 2B), and polyvinyl acetate phthalate(PVAP, FIG. 2C). The total drug species are represented by open circleswith error bars, and the free drug species are represented by closedcircles with error bars.

FIGS. 3A-3D are graphs showing the dissolution rate in gastric media forsolid dispersion formulations having 50% (w/w) loading of compound 1 anda gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 13 minutes. Thefollowing solid dispersion formulations were tested: cellulose acetatephthalate (CAP, FIG. 3A), hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M, FIG. 3B), methacrylic acid-methylmethacrylate copolymer (Eudragit® L 100, FIG. 3C), and polyvinyl acetatephthalate (PVAP, FIG. 3D). The total drug species are represented byopen circles with error bars, and the free drug species are representedby closed circles with error bars. The solubility of unformulatedcompound 1 in the gastric and FaSSIF media is shown in FIG. 3A.

FIGS. 4A-4B are graphs showing results from computer modeling offraction absorbed (FIG. 4A) and fed-fasted ratio (FIG. 4B) for 20%, 35%,and 50% (w/w) loading of compound 1. Data are shown for solid dispersionformulations of carboxymethylethyl cellulose (CMEC), hydroxypropylmethylcellulose acetate succinate M grade (HPMCAS-M), cellulose acetatephthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylicacid-methyl methacrylate copolymer (Eudragit® L 100), polyethyleneglycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®),polyvinylpyrrolidone vinylacetate copolymer (PVP-VA), andhydroxypropylmethyl cellulose phthalate (HPMCP-H44), and for crystallinecompound 1 (API).

FIGS. 5A-5B are graphs showing the dissolution rate in gastric media forsolid dispersion formulations having 20% (w/w) loading of compound 1 anda gastric-to-FaSSIF (pH 1.0-to-6.5) media transition at 30 minutes. Thefollowing solid dispersion formulations were tested: cellulose acetatephthalate (CAP, FIG. 5A) and hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M, FIG. 5B). The total drug species arerepresented by open circles with error bars, and the free drug speciesare represented by closed circles with error bars.

FIG. 6 is a graph showing modulated differential scanning calorimetrymeasurements at ambient relative humidity for solid dispersionformulations having 20% (w/w) loading of compound 1. Glass transitiontemperature T_(g) is shown for formulations of carboxymethylethylcellulose (CMEC), hydroxypropylmethyl cellulose acetate succinate Mgrade (HPMCAS-M), cellulose acetate phthalate (CAP), and polyvinylacetate phthalate (PVAP).

FIG. 7 is a graph showing powder x-ray diffraction measurements forcrystalline compound 1 and solid dispersion formulations having 20%(w/w) loading of compound 1 with hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M) or cellulose acetate phthalate (CAP).

FIGS. 8A-8C are graphs showing mean concentration of compound 1 inplasma for various formulations in an in vivo studies in rats. Data areshown for formulation 1 having cellulose acetate phthalate (CAP) (FIG.8A), formulation 2 having hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M) (FIG. 8B), and control (FIG. 8C) with dosesof 10 mg/kg, 30 mg/kg, and 100 mg/kg.

FIGS. 9A-9C are graphs showing mean concentration of compound 1 inplasma for various doses in an in vivo study in rats. Data are shown forformulations 1, 2, and control with doses of 10 mg/kg (FIG. 9A), 30mg/kg (FIG. 9B), and 100 mg/kg (FIG. 9C).

FIG. 10 is a graph showing mean concentration of compound 1 in plasmafor various formulations in an in vivo study in dogs with a 10 mg/kgdose. Data are shown for 20% (w/w) compound 1 with hydroxypropylmethylcellulose acetate succinate M grade (HPMCAS-MG, Group 2) or celluloseacetate phthalate (CAP, Group 3) and control (Group 1).

FIGS. 11A-11B are graphs comparing AUC₀₋₂₄ values for two formulationsin fasted or fed conditions. Data are provided for compound 1 (freebase) in a spray dried dispersion (SDD) formulation (“SDD”) to compound1 (HCl salt) in a micronized formulation (“Micronized”). FIG. 11A showsthe ratio of AUC₀₋₂₄ for fasted to fed conditions (i.e., [AUC₀₋₂₄fasted]/[AUC₀₋₂₄ fed]) for SDD or Micronized. FIG. 11B shows the ratioof AUC₀₋₂₄ for SDD to Micronized (i.e., [AUC₀₋₂₄ SDD]/[AUC₀₋₂₄Micronized]) for fasted or fed conditions.

FIG. 12 is a series of box plots showing the mean, median anddistributions of the AUC_(0-∞) for all treatments in groups 1 and 2 ofExamples 10 and 11, comparing treatment with the hot melt extrusion(HME) formulation under fasted or fed conditions and, separately,comparing treatment with the HME or SDD formulations under fedconditions. Formulation details are provided in Examples 7 and 8.

FIG. 13 is a series of box plots showing the mean, median anddistributions of the C_(max) for all treatments in groups 1 and 2 ofExamples 10 and 11, comparing treatment with the HME formulation underfasted or fed conditions and, separately, comparing treatment with theHME or SDD formulations under fed conditions. Formulation details areprovided in Examples 7 and 8.

DETAILED DESCRIPTION

The invention provides methods for treating conditions related to N-typecalcium channels, involving administration of1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one (compound 1), ametabolite thereof (e.g., 1-(3,3-diphenylpropanoyl)piperazine (compound2), or a salt thereof. Non-limiting examples of conditions treatable bythis administration are pain and epilepsy.

Compound 1 is a potent and selective N-type calcium channel antagonist,and doses of up to 1,600 mg provided no adverse effects. Yet, compound 1is also known to have decreased oral bioavailability in the fastedstate, as compared to the fed state. Accordingly, the invention providesformulations to increase the oral bioavailability or to reducepatient-to-patient variability in pharmacokinetic behavior of compound1, compound 2, or a salt thereof. Generally, amorphous forms of a drugare more readily absorbed within the gastric and intestinal system and,thus, have increased bioavailability, as compared to crystalline formsof the drug. These formulations include use of a solid dispersion systemto provide a matrix polymer capable of maintaining therapeuticallyeffective amounts of compound 1, compound 2, or a salt thereof, in anamorphous form.

Previously Determined Characteristics of Compound 1

Compound 1 has the following previously determined characteristics:

(i) physical appearance: white to off-white powder;

(ii) solubility: slightly soluble in water (0.2 μg/ml to 2.0 μg/ml at pHof 6.8, 0.03 μg/ml at pH of 6.5, 1.5 μg/ml at pH of 6.5 in FaSSIF, and55 μg/ml at pH of 1.0) and soluble in acetone (up to 50 mg/ml),propylene glycol, ethanol, and tetrahydrofuran;

(iii) pKa: 5.4;

(iv) log P: 2.6;

(v) M.P.: 123° C. (for free base) and 126° C. (for HCl salt);

(vi) T_(g): 41.6° C.;

(vii) hygroscopicity (for free base): 0.09% at 70% relative humidity(RH);

(viii) potential isomerism: none;

(ix) T_(max) (for HCl salt): <2 hours (fasted state), 2-5 hours (fedstate with normal fat meal), and 4-5 hours (fed state with high fatmeal); and

(x) t_(1/2) for absorption (for HCl salt): 0.05-0.17 hours (fastedstate), 0.5-1.6 hours (fed state with normal fat meal), and 0.8-2.8hours (fed state with high fat meal). The fed-fasted pharmacokineticdata were collected using a “normal fat” meal consisting of toast with 1pat of butter, a banana, 2% milk, apple juice, and Honey Nut Cheerios®,where the meal has about 501 calories with 99 calories from fat, 346calories from carbohydrates, and 56 calories from protein; and using a“high fat” meal consisting of 2 eggs fried in butter, 2 strips of bacon,2 slices of toast with butter, 4 ounces of hash brown potatoes and 8ounces of whole milk, where the meal has about 1,000 calories with500-600 calories from fat, 250 calories from carbohydrates, and 150calories from protein.

The relative oral bioavailability of compound 1 (HCl salt) has beenpreviously determined in various fed and fasted states in a micronizedformulation. This micronized formulation included the following for a100 mg dose in a #1 HPMC (white opaque) capsule: compound 1 HClmicronized (100.00 mg), Lactose Fast Flo® Fast Flo® composed of aspray-dried mixture of crystalline and amorphous lactose monohydrate(184.80 mg); sodium starch glycolate (19.20 mg); polysorbate 80 (14.40mg); purified water (used as the granulating fluid and was removedduring processing) (QS); and magnesium stearate (1.60 mg), where theresultant fill weight was 320.00 mg. For a 25 mg dose in a #1 gelatin(white opaque) capsule, the formulation included the following: compound1 HCl micronized (25.00 mg), Lactose Fast Flo® Fast Flo® composed of aspray-dried mixture of crystalline and amorphous lactose monohydrate(264.60 mg); sodium starch glycolate (19.20 mg); polysorbate 80 (9.60mg); purified water (used as the granulating fluid and was removedduring processing) (QS); and magnesium stearate (1.60 mg), where theresultant fill weight was 320.00 mg.

For the micronized formulation, typical values for relativebioavailability included 0.682 for a fasted state relative to a fedstate with a normal fat meal; 1.48 for a 25 mg capsule relative to a 100mg capsule; 5.60 for a fed state with a high fat meal relative to a fedstate with a normal fat meal; and

$1 - {0.363 \times {\log_{10}\left( \frac{dose}{100} \right)}}$

as a function of dose (mg) relative to a 100 mg dose. Typical valueswere computed as 100%×√ω², where ω²=variance (eta), and 68% of the studypopulation were within the range of these typical values. Relativebioavailability values derived from the provided typical values areprovided in Table 1.

TABLE 1 Meal* Dosage form Dose (mg) Fasted Normal fat High fat 100 mg100 0.682 1.000 5.600 capsule 200 0.607 0.891 4.988 400 0.533 0.7814.376 800 0.458 0.672 3.764 1,600 0.384 0.563 3.152 25 mg 25 1.230 NA10.10 capsule 50 1.120 NA 9.19 100 1.009 NA 8.29 200 0.899 NA 7.38 4000.789 NA 6.48 800 0.678 NA 5.57 1,600 0.568 NA 4.67 *Values areexpressed relative to the 100 mg dose administered with a normal fatmeal.

Synthesis of Compound 1

Compound 1, or a salt thereof, can be synthesized by any useful method,including those described in U.S. Pat. Nos. 6,294,533; 6,387,897;6,492,375; 6,617,322; 6,949,554; 6,951,862; and 7,064,128; and U.S.Patent Publication Nos. 2006/0084660 and 2004/0259866, incorporatedherein by reference in their entirety.

Scheme 1 provides an exemplary schematic for the synthesis of compound 1(free base). Briefly, the first and second steps provide purified3,3-diphenylpropionic acid, and these steps can optionally include arecrystallization step in ethyl acetate/heptanes (70/30). Then, thethird step provides compound 1, and this step can optionally include useof a toluene azeotrope to remove residual solvents, such as ethanol,tetrahydrofuran (THF), ethyl acetate, commercial grade heptanes,toluene, or isopropanol.

Synthesis of Compound 2

Compound 2, or a salt thereof, can be synthesized by any useful method,including those described in U.S. Pat. Nos. 6,011,035; 6,951,862; and7,186,726; U.S. Patent Application Publication Nos. 2006/0084660 and2004/0259866; International Publications Nos. WO 2008/066803, WO2011/006073, and WO 2007/118323; J. Am. Chem. Soc. 77:3142, 1955; and J.Am. Pharm. Assoc. 46:279, 1957; incorporated herein by reference intheir entirety.

Scheme 2 provides an exemplary schematic for the synthesis of compound 2(free base). Briefly, the first step provides a protected carbamatecompound. The second step provides compound 2. These steps canoptionally include a purification step (e.g., where the startingmaterial, 3,3-diphenylpropanoic acid, can be optionally purified, asshown in Scheme 1), a recrystallization step in ethyl acetate/heptanes(e.g., in a ratio of 70/30), or use of a toluene azeotrope to removeresidual solvents, such as ethanol, tetrahydrofuran (THF), ethylacetate, commercial grade heptanes, toluene, or isopropanol.

Pharmaceutically Acceptable Matrix Polymer

Pharmaceutically acceptable matrix polymers include one or more polymerscapable of forming a solid dispersion with compound 1, compound 2, or asalt thereof. Two or more matrix polymers can be used to together andcan optionally include one or more surfactants and/or plasticizers.Generally, optimal T_(g) values include from 50° C. to 180° C., which ishigher than the melting temperature of compound 1 or compound 2 butlower than the temperature at which compound 1 or compound 2 decomposes.Exemplary T_(g) values for matrix polymers are from 50° C. to 180° C.(e.g., from 50° C. to 170° C., from 50° C. to 160° C., from 50° C. to150° C., from 50° C. to 145° C., from 50° C. to 140° C., from 50° C. to135° C., from 50° C. to 130° C., from 50° C. to 125° C., from 50° C. to120° C., from 50° C. to 115° C., from 50° C. to 110° C., from 50° C. to105° C., from 50° C. to 100° C., from 50° C. to 95° C., from 50° C. to90° C., from 50° C. to 85° C., from 50° C. to 80° C., from 50° C. to 75°C., from 50° C. to 70° C., from 50° C. to 65° C., from 50° C. to 60° C.,from 75° C. to 180° C., from 75° C. to 170° C., from 75° C. to 160° C.,from 75° C. to 150° C., from 75° C. to 145° C., from 75° C. to 140° C.,from 75° C. to 135° C., from 75° C. to 130° C., from 75° C. to 125° C.,from 75° C. to 120° C., from 75° C. to 115° C., from 75° C. to 110° C.,from 75° C. to 105° C., from 75° C. to 100° C., from 75° C. to 95° C.,from 75° C. to 90° C., from 75° C. to 85° C., from 75° C. to 80° C.,from 80° C. to 180° C., from 80° C. to 170° C., from 80° C. to 160° C.,from 80° C. to 150° C., from 80° C. to 145° C., from 80° C. to 140° C.,from 80° C. to 135° C., from 80° C. to 130° C., from 80° C. to 125° C.,from 80° C. to 120° C., from 80° C. to 115° C., from 80° C. to 110° C.,from 80° C. to 105° C., from 80° C. to 100° C., from 80° C. to 95° C.,from 80° C. to 90° C., from 80° C. to 85° C., from 85° C. to 180° C.,from 85° C. to 170° C., from 85° C. to 160° C., from 85° C. to 150° C.,from 85° C. to 145° C., from 85° C. to 140° C., from 85° C. to 135° C.,from 85° C. to 130° C., from 85° C. to 125° C., from 85° C. to 120° C.,from 85° C. to 115° C., from 85° C. to 110° C., from 85° C. to 105° C.,from 85° C. to 100° C., from 85° C. to 95° C., from 85° C. to 90° C.,from 90° C. to 180° C., from 90° C. to 170° C., from 90° C. to 160° C.,from 90° C. to 150° C., from 90° C. to 145° C., from 90° C. to 140° C.,from 90° C. to 135° C., from 90° C. to 130° C., from 90° C. to 125° C.,from 90° C. to 120° C., from 90° C. to 115° C., from 90° C. to 110° C.,from 90° C. to 105° C., from 90° C. to 100° C., from 90° C. to 95° C.,from 95° C. to 180° C., from 95° C. to 170° C., from 95° C. to 160° C.,from 95° C. to 150° C., from 95° C. to 145° C., from 95° C. to 140° C.,from 95° C. to 135° C., from 95° C. to 130° C., from 95° C. to 125° C.,from 95° C. to 120° C., from 95° C. to 115° C., from 95° C. to 110° C.,from 95° C. to 105° C., from 95° C. to 100° C., from 100° C. to 180° C.,from 100° C. to 170° C., from 100° C. to 160° C., from 100° C. to 150°C., from 100° C. to 145° C., from 100° C. to 140° C., from 100° C. to135° C., from 100° C. to 130° C., from 100° C. to 125° C., from 100° C.to 120° C., from 100° C. to 115° C., from 100° C. to 110° C., from 100°C. to 105° C., from 110° C. to 180° C., from 110° C. to 170° C., from110° C. to 160° C., from 110° C. to 150° C., from 110° C. to 145° C.,from 110° C. to 140° C., from 110° C. to 135° C., from 110° C. to 130°C., from 110° C. to 125° C., from 110° C. to 120° C., from 110° C. to115° C., from 120° C. to 180° C., from 120° C. to 170° C., from 120° C.to 160° C., from 120° C. to 150° C., from 120° C. to 145° C., from 120°C. to 140° C., from 120° C. to 135° C., from 120° C. to 130° C., from120° C. to 125° C., from 125° C. to 180° C., from 125° C. to 170° C.,from 125° C. to 160° C., from 125° C. to 150° C., from 125° C. to 145°C., from 125° C. to 140° C., from 125° C. to 135° C., from 125° C. to130° C., from 130° C. to 180° C., from 130° C. to 170° C., from 130° C.to 160° C., from 130° C. to 150° C., from 130° C. to 145° C., from 130°C. to 140° C., from 130° C. to 135° C., from 135° C. to 150° C., from135° C. to 145° C., from 135° C. to 140° C., from 150° C. to 180° C.,from 150° C. to 170° C., from 150° C. to 160° C., and from 175° C. to180° C.).

Exemplary T_(g) values for a solid dispersion including compound 1 orcompound 2 and one or more matrix polymers are from 80° C. to 150° C.(e.g., from 80° C. to 145° C., from 80° C. to 140° C., from 80° C. to135° C., from 80° C. to 130° C., from 80° C. to 125° C., from 80° C. to120° C., from 80° C. to 115° C., from 80° C. to 110° C., from 80° C. to105° C., from 80° C. to 100° C., from 80° C. to 95° C., from 80° C. to90° C., from 80° C. to 85° C., from 85° C. to 150° C., from 85° C. to145° C., from 85° C. to 140° C., from 85° C. to 135° C., from 85° C. to130° C., from 85° C. to 125° C., from 85° C. to 120° C., from 85° C. to115° C., from 85° C. to 110° C., from 85° C. to 105° C., from 85° C. to100° C., from 85° C. to 95° C., from 85° C. to 90° C., from 90° C. to150° C., from 90° C. to 145° C., from 90° C. to 140° C., from 90° C. to135° C., from 90° C. to 130° C., from 90° C. to 125° C., from 90° C. to120° C., from 90° C. to 115° C., from 90° C. to 110° C., from 90° C. to105° C., from 90° C. to 100° C., from 90° C. to 95° C., from 95° C. to150° C., from 95° C. to 145° C., from 95° C. to 140° C., from 95° C. to135° C., from 95° C. to 130° C., from 95° C. to 125° C., from 95° C. to120° C., from 95° C. to 115° C., from 95° C. to 110° C., from 95° C. to105° C., from 95° C. to 100° C., from 120° C. to 150° C., from 120° C.to 145° C., from 120° C. to 140° C., from 120° C. to 135° C., from 120°C. to 130° C., from 120° C. to 125° C., from 125° C. to 150° C., from125° C. to 145° C., from 125° C. to 140° C., from 125° C. to 135° C.,from 125° C. to 130° C., from 130° C. to 150° C., from 130° C. to 145°C., from 130° C. to 140° C., from 130° C. to 135° C., from 135° C. to150° C., from 135° C. to 145° C., and from 135° C. to 140° C.).

Exemplary matrix polymers are one or more of ethyl cellulose (T_(g)=133°C.), cellulose acetate phthalate (CAP, T_(g)=171° C.),hydroxypropylmethyl cellulose acetate (T_(g)=177° C.),hydroxypropylmethyl cellulose acetate succinate (HPMCAS, T_(g)=115° C.),hydroxypropylmethyl cellulose phthalate (HPMCP, T_(g)=133° C.),polyvinylpyrrolidone (T_(g)=174° C.), crospovidone (T_(g)=190° C. to195° C.), polyvinyl alcohol (T_(g)=75° C.), and polyvinyl acetatephthalate (T_(g)=55° C.). Exemplary solid dispersions are those having20% (w/w) of compound 1 and CMEC (T_(g)=89.4° C.), HPMCAS-M (T_(g)=91.3°C.), CAP (T_(g)=129.9° C.), or PVAP (T_(g)=116.1° C.).

Examples of matrix polymers which can be used in the formulations of theinvention are, without limitation, cellulose derivatives, polyacrylates,polyvinyl pyrrolidones, polyvinyl acetates, and copolymers thereof.

Cellulose Derivatives

The formulations of the invention can include one or more cellulosederivatives. Cellulose derivatives generally include those having anynumber of modifications to the free hydroxyl groups in cellulose.

In some examples, the cellulose derivative is a cellulose acetate havingfrom 10% to 50% acetyl. Referring to cellulose derivatives, % refers tothe proportion of the free hydroxyl groups esterified with a functionalgroup. For example, “10% acetyl” refers to a derivative having 10% ofthe free hydroxyl groups in cellulose esterified with an acetyl group.

Particular examples of cellulose acetates are cellulose acetatephthalates (CAP), such as those having 35% phthalyl, 24% acetyl(available as Cellacefate from Eastman Chemical Company, Kingsport,Tenn.); methylcellulose acetate phthalates; hydroxypropylmethylcellulose acetates; and hydroxypropylmethyl cellulose acetate succinates(HPMCAS), such as M grade having 9% acetyl/11% succinoyl (e.g., HPMCAShaving a mean particle size of 5 μm (i.e., HPMCAS-MF, fine powder grade)or having a mean particle size of 1 mm (i.e., HPMCAS-MG, granulargrade)), H grade having 12% acetyl/6% succinoyl (e.g., HPMCAS having amean particle size of 5 μm (i.e., HPMCAS-HF, fine powder grade) orhaving a mean particle size of 1 mm (i.e., HPMCAS-HG, granular grade)),and L grade having 8% acetyl/15% succinoyl (e.g., HPMCAS having a meanparticle size of 5 μm (i.e., HPMCAS-LF, fine powder grade) or having amean particle size of 1 mm (i.e., HPMCAS-LG, granular grade)).

Additional exemplary cellulose derivatives are alkyl celluloses, such asmethyl cellulose (Methocel™ A) or ethylcellulose (Ethocel®);hydroxyalkyl celluloses, such as hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC, e.g., low-substituted HPChaving 11% hydroxypropyl or 8% hydroxypropyl), and hydroxybutylcellulose; hydroxyalkylalkyl celluloses, such as hydroxyethylmethylcellulose and hydroxypropylmethyl cellulose (hypromellose, HPMC, e.g.,those having about 19-24% methoxyl/7-12% hydroxypropxyl (Methocel™ K,including those having apparent viscosity (2% in water at 20° C.) of80-120 cP (Methocel™ K100), 3,000-5,600 cP (Methocel™ K4M),11,250-21,000 cP (Methocel™ K15M), 80,000-120,000 cP (Methocel™ K100M),available from Dow Chemical Co.), 28-30% methoxyl/7-12% hydroxypropxyl(Methocel™ E, including those having apparent viscosity (2% in water at20° C.) of 3,000-5,600 cP (Methocel™ E4M) and 7,500-14,000 cP (Methocel™E10M), also available from Dow Chemical Co.), 23% methoxyl/10%hydroxypropxyl (Metolose® SR, available from Shin-Etsu Chemical Co.,Ltd., Tokyo, Japan), 23%-29% methoxyl/8%-9% hydroxypropxyl (Metolose®,also available from Shin-Etsu Chemical Co., Ltd.), 29% methoxyl/9%hydroxypropxyl (Hypromellose USP, substitution 2910), and 23%methoxyl/6% hydroxypropxyl (Hypromellose USP, substitution 2208));hydroxyalkylalkyl cellulose esters, such as hydroxypropylmethylcellulose phthalate (HPMCP) (e.g., HP 55 grade having 31% nominalphthalyl content and HP-55S or HP-50 grades having 24% nominal phthalylcontent); carboxyalkyl celluloses, such as carboxymethyl cellulose andalkali metal salts thereof, such as sodium salts; carboxyalkylalkylcelluloses, such as carboxymethylethyl cellulose; and carboxyalkylcellulose esters, such as carboxymethyl cellulose butyrate,carboxymethyl cellulose propionate, carboxymethyl cellulose acetatebutyrate, and carboxymethyl cellulose acetate propionate.

Any of the cellulose derivatives herein can be further cross-linked orcopolymerized (e.g., with any matrix polymer described herein).

Polyacrylates

The formulations of the invention can include one or more polyacrylatesor copolymers thereof.

Exemplary polyacrylates are polymethacrylates; methacrylate copolymers,such as methacrylic acid-methyl methacrylate copolymers having a 1:1ratio of free carboxyl groups to ester groups (e.g., Eudragit® L 100, MW˜125,000 g/mol) and a 1:2 ratio of free carboxyl groups to ester groups(Eudragit® S 100, MW ˜125,000 g/mol), dimethylaminoethylmethacrylate-butyl methacrylate-methyl methacrylate copolymers (e.g.,having a ratio of 2:1:1 of dimethylaminoethyl methacrylate-butylmethacrylate-methyl methacrylate and in powder, granule, or solutionforms, i.e., Eudragit® E PO, Eudragit® E 100, or Eudragit® E 12.5,respectively), and diethylaminoethyl methacrylic acid-methylmethacrylate copolymers (e.g., Eudragit® E); and ethacrylate copolymers,such as methacrylic acid ethacrylate copolymers having a 50:50 ratio ofmethacrylic acid to ethacrylate (e.g., Kollicoat® MAE 100P or Eudragit®L100-55, MW ˜320,000 g/mol)

Polyvinyl Pyrrolidones and Polyvinyl Acetates

The formulations of the invention can include one or more polyvinylpyrrolidones, polyvinyl acetates, or copolymers thereof.

Exemplary polyvinyl pyrrolidones and polyvinyl acetates are polyvinylpyrrolidones (e.g., povidone, PVP, or soluble povidone) having molecularweights of about 2,500 (Kollidon®12 PF, weight-average molecular weightbetween 2,000 to 3,000), about 9,000 (Kollidon®17 PF, weight-averagemolecular weight between 7,000 to 11,000), about 25,000 (Kollidon®25,weight-average molecular weight between 28,000 to 34,000), about 50,000(Kollidon®30, weight-average molecular weight between 44,000 to 54,000),and about 1,250,000 (Kollidon®90 or Kollidon®90F, weight-averagemolecular weight between 1,000,000 to 1,500,000); polyvinyl acetateesters, such as polyvinyl acetate phthalate (PVAP); polyethyleneglycol-polyvinyl acetate copolymers, such as polyethyleneglycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®); andpolyvinylpyrrolidone-polyvinyl acetate copolymers (PVP-VA), such asthose having a 60:40 ratio of N-vinyl-2-pyrrolidone to vinyl acetate(copovidone, also available as Kollidon® VA 64) and a 20:80 ratio ofN-vinyl-2-pyrrolidone to vinyl acetate (Kollidon® SR).

Hydrophobic-Lipophilic Balance

The matrix polymers, plasticizers, and surfactants used in theformulations of the invention can be characterized by thehydrophobic-lipophilic balance (“HLB”). HLB generally provides thedegree of hydrophobicity or lipophilicity for a given molecule. HLB canbe determined by any useful method, including the formula HLB=20×Mh/M,where Mh is the molecular mass of the hydrophilic region of the moleculeand M is the molecule mass of the molecule, and the formulaHLB=7+Σ_(i)N_(i) ^(h)−Σ_(i)N_(i) ^(l), where i is the number of groups,N_(i) ^(h) is a value for each i^(th) hydrophilic group, and N_(i) ^(l)is the value for each i^(th) lipophilic group. Values of N^(h) and N^(l)depend on the type of hydrophilic and lipophilic group, respectively.Exemplary values for N^(h) include 38.7 for —SO₄Na, 21.1 for —CO₂K, 19.1for —CO₂Na, 9.4 for tertiary amine N, 6.8 for ester (sorbitan ring), 2.4for ester (free), 2.1 for —CO₂H, 1.9 for —OH (free), 1.3 for —O—, 0.5for —OH (sorbitan ring), and 0.33 for —(CH₂CH₂O)—; and for N^(l) include−1.66 for benzyl, −0.475 for —CH—, —CH₂—, —CH₃, and —CH—, and −0.13 for—(CH₂CH₂CH₂O)—.

Plasticizers

The formulations of the invention optionally include one or moreplasticizers. Generally, plasticizers can be used to reduce the glasstransition temperature T_(g) or to decrease viscosity of the mixture ofcompound 1, compound 2, or a salt thereof, with the matrix polymer.Exemplary plasticizers are polyalkylene oxides, such as polyethyleneglycols (e.g., PEG 300, PEG 400, PEG 4000, or PEG 8000) andpolypropylene glycols; copolymers of ethylene oxide and propylene oxide,such as ethoxylated propoxylated block copolymers having the formulaH(OCH₂CH₂)_(a)(OCHCH₃CH₂)_(b)(OCH₂CH₂)_(a)OH, where a is about 12 and bis about 20 (Poloxamer® 124), where a is about 38 and b is about 29,where a is about 80 and b is about 27 (Poloxamer® 188), where a is about64 and b is about 37 (Poloxamer® 237), where a is about 141 and b isabout 44 (Poloxamer® 338), where a is about 49 and b is about 57, andwhere a is about 101 and b is about 56 (Poloxamer® 407); andpolyethoxylated glyceryl esters, such as polyoxyl 35 castor oil(Cremophor® EL, HLB=12 to 14) and polyoxyl 40 castor oil having 40-45moles of ethylene oxide (Cremophor® RH-40, HLB=14 to 16).

Surfactants

Exemplary surfactants are liquid and solid polyethoxylated esters offatty acids, such as polyoxyl 40 stearate (Myrj® 52,hydrophobic-lipophilic balance (“HLB”)=17), PEG 400 monostearate, alsoknown as polyoxyl 8 stearate (Myrj® 45, HLB=11), and PEG 660hydroxystearate, also known as PEG 15 hydroxystearate (Solutol® HS15,HLB=14 to 16); polyethoxylated alkyl ethers, such as polyoxyl 10 oleylether (Brij® 97, HLB=12.4) and PEG 25 cetostearyl ether (Cremophor® A25, HLB=15 to 17); polyethoxylated sorbitan esters, such as polysorbate20 (Tween® 20, HLB=15) and polysorbate 80 (Tween® 80, HLB=11.5);polyethoxylated glyceryl esters having high HLB values (e.g., from 10 to20), such as polyoxyl 35 castor oil (Cremophor® EL, HLB=12 to 14) andpolyoxyl 40 castor oil having 40-45 moles of ethylene oxide (Cremophor®RH-40, HLB=14 to 16); polyethoxylated glyceryl esters of fatty acidshaving high HLB values (e.g., from 10 to 20), such as a mixture of PEG 6caprylic/capric glyceryl esters having <2% C₆/50%-80% C₈/20%-50% C₁₀/<3%C₁₂/<1% C₁₄ (Softigen® 767, HLB=19), a mixture of PEG 8 caprylic/capricglyceryl esters having 50%-80% C₈/20%-50% C₁₀/<3% C₁₂/<1% C₁₈(Labrasol®, HLB=14), a mixture of PEG 32 lauryl glyceryl esters having40%-50% C₁₂/14%-24% C₁₄/4%-10% C₈/3-9% C₁₀/4%-14% C₁₆/5%-15% C₁₈(Gelucire® 44/14, HLB=14), and a mixture of PEG 32 stearyl glycerylesters having 40%-50% C₁₆/48%-58% C₁₈ (Gelucire® 50/13, HLB=13);polyethoxylated vitamin analogs, such as D-alpha-tocopheryl PEG 1000succinate (HLB=13); and ethoxylated propoxylated block copolymers havingformula H(OCH₂CH₂)_(a)(OCHCH₃CH₂)_(b)(OCH₂CH₂)_(a)OH, where a is about12 and b is about 20 (Poloxamer® 124), where a is about 38 and b isabout 29, where a is about 80 and b is about 27 (Poloxamer® 188), wherea is about 64 and b is about 37 (Poloxamer® 237), where a is about 141and b is about 44 (Poloxamer® 338), where a is about 49 and b is about57, and where a is about 101 and b is about 56 (Poloxamer® 407).

Tocopheryl polyethylene glycol succinate (tocopheryl PEG-1000 succinate)and related pegylated vitamin E compounds can be used in thepharmaceutical composition of the invention. Tocopheryl PEG-1000succinate has the following structure:

where n is an integer (e.g., the molecular weight is about 1513 fortocopheryl PEG-1000 succinate).

Related pegylated vitamin E compounds include additives formed usingdifferent diacid linkers, different length polyethylene glycol tails,and different isoforms (e.g. α-, β-, γ-, or δ-) of tocopherol,tocomonoenol, tocodienol, and tocotrienol. These include α-tocopherol,α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol,β-tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol,γ-tocomonoenol, γ-tocodienol, γ-tocotrienol, δ-tocopherol,δ-tocomonoenol, δ-tocodienol, δ-tocotrienol, and any stereoisomerthereof. Suitable vitamin E compounds of the present invention alsoinclude desmethyl-tocopherol, desmethyl-tocomonoenol,desmethyl-tocodienol, desmethyl-tocotrienol, and any stereoisomerthereof. Furthermore, when a compound disclosed herein contains one ormore chiral atoms where stereochemistry is unspecified, it will beunderstood that each stereoisomer of the compound is individuallydisclosed as if the structure of each stereoisomer were explicitlydrawn. In certain embodiments of the invention, the vitamin E compoundmay be a naturally-occurring D-stereoisomer of vitamin E.

The vitamin E moieties of the present invention may be naturallyoccurring or synthetic. Certain embodiments of the invention include anaturally occurring vitamin E compound such as an extract from a foodsource. For example, α-tocopherol, α-tocotrienol, β-tocopherol,β-tocotrienol, γ-tocopherol, γ-tocotrienol, δ-tocopherol, andδ-tocotrienol are available naturally from fortified cereals, greenvegetables, nuts, seeds, and vegetable oils. Methods of extractingvitamin E from natural sources have been described, for example, in U.S.Pat. Nos. 6,743,450; 6,838,104; 7,161,055; and 7,544,822, which arehereby incorporated by reference.

The pegylated vitamin E compound can include synthetic vitamin Emoieties. An exemplary method for making α-tocopherol is the reaction oftrimethylhydroquinone (TMHQ) with iso-phytol(3,7,11,15-tetramethylhexadec-1-en-3-ol) in a condensation reaction witha catalyst. It will be apparent to one skilled in the art that othertocopherol, tocomonoenol, tocodienol, and tocotrienol isoforms and theirderivatives can also be prepared using a similar strategy starting fromappropriate precursors. For example, the starting compounds may be TMHQand 3,7,11,15-tetramethylhexadec-2-en-1-ol. An additional method ofmaking vitamin E with isophytol under relatively mild conditions hasbeen described by Wehrli et al., J. Org. Chem. 36:2910 (1971). Methodsfor synthesizing unsaturated side chains of vitamin E are described inU.S. Pat. No. 4,168,271, which is hereby incorporated by reference.Additional methods of synthesizing vitamin E side chains have beenreviewed by Stalla-Bourdillon, Ind. Chim. Belg. 35, 13 (1970).Additional methods of synthesizing tocopherols are described in U.S.Pat. Nos. 5,523,420 and 6,005,122, each of which is incorporated hereinby reference. Additional methods of synthesizing tocotrienols aredescribed in U.S. Pat. No. 7,038,067, which is hereby incorporated byreference.

Pegylated vitamin E compounds can include different linkers, forexample, dicarboxylic acids (e.g., succinic acid, sebacic acid,dodecanedioic acid, suberic acid, or azelaic acid, citraconic acid,methylcitraconic acid, itaconic acid, maleic acid, glutaric acid,glutaconic acid, fumaric acids, and phthalic acids). Exemplarytocopherol polyethylene glycol diesters are TPGS-1000, tocopherolsebacate polyethylene glycol, tocopherol dodecanodioate polyethyleneglycol, tocopherol suberate polyethylene glycol, tocopherol azelaatepolyethylene glycol, tocopherol citraconate polyethylene glycol,tocopherol methylcitraconate polyethylene glycol, tocopherol itaconatepolyethylene glycol, tocopherol maleate polyethylene glycol, tocopherolglutarate polyethylene glycol, tocopherol glutaconate polyethyleneglycol, and tocopherol phthalate polyethylene glycol.

The PEG moiety of the pegylated vitamin E compound can be anypolyethylene glycol or derivative thereof, and can have a molecularweight of 200-6,000 kDa (e.g., 400-4,000 kDa, 500-2,000 kDa, 750-1,500kDa, 800-1,200 kDa, 900-1,100 kDa, or about 1,000 kDa). PEG derivativesinclude, for example, methylated PEG, polypropylene glycol (PPG),PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, PEG-OMe, as well asother ethers, branched PEGs, and PEG copolymers (e.g.,PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, andPPG-PEG-PPG-2000).

Any known source of pegylated vitamin E compound can be used in thepresent invention. Pegylated vitamin E compounds typically have an HLBvalue of between about 16 and about 18 (e.g., between 18 and 18). Anexemplary pegylated vitamin E compound is tocopheryl PEG-1000 succinate(also referred to herein as “TPGS 1000”), which has a PEG moiety havinga molecular weight of 1,000 kDa. A food grade TPGS 1000 is available,for example, under the trade name Eastman Vitamin E TPGS® (EastmanChemical Company, Kingsport, Tenn.). This TPGS is water-soluble form ofnatural-source vitamin E, which is prepared by esterification ofcrystalline D-α-tocopheryl acid succinate with polyethylene glycol 1000(PEG 1000), and contains between 260 and 300 mg/g total tocopherol.Another exemplary pegylated vitamin E compound is Water Soluble NaturalVitamin E (ZMC-USA, The Woodlands, Tex.). Methods of preparing pegylatedvitamin E compounds are described in U.S. Pat. Nos. 2,680,749 and3,102,078 and in U.S. Publication Nos. 2007/0184117 and 2007/0141203,which are herein incorporated by reference.

Pegylated vitamin E compounds also include chromanol derivatives (e.g.,6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate),steroid derivatives (e.g., cholesteryl PEG-1000 succinate, cholic acidPEG-1000, dihydrocholic acid PEG-1000, litho-cholic acid PEG-1000,ursodeoxycholic acid PEG-1000, chenodeoxycholic acid PEG-1000), andothers (e.g., indomethacin PEG-1000, chromone-2-carboxylic acidPEG-1000, chromone-2-carboxylic acid PEG-1100-OMe, chromone-2-carboxylicacid PEG-1500, chromone-2-carboxylic acid PEG-2000, naproxen PEG-1000,probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000,5-(4-chlorophenyl)-2-furoic acid PEG-1000, probenecid tocopherylPEG-1000 succinate, lithocholic acid PEG-1000, and chromone-3-carboxylicacid PEG-1000, 7-hydroxy-coumarinyl-4-acetic acid PEG-1000).

Pharmaceutically Acceptable Excipients

Pharmaceutically acceptable excipients include one or more otheringredient capable of maintaining compound 1, compound 2, or a saltthereof, in a substantially amorphous form. In particular embodiments,the excipient is a pharmaceutically acceptable matrix polymer, asdescribed herein.

Exemplary excipients are antiadherents, antioxidants, binders, coatings,compression aids, disintegrants, dyes (colors), emollients, emulsifiers,fillers (diluents), film formers or coatings, flavors, fragrances,glidants (flow enhancers), lubricants, preservatives, printing inks,sorbents, suspensing or dispersing agents, sweeteners, and waters ofhydration. Additional non-limiting exemplary excipients are: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

These excipients may be, for example, inert diluents or fillers (e.g.,sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starchesincluding potato starch, kaolin, calcium carbonate, sodium chloride,lactose, calcium phosphate, calcium sulfate, and sodium phosphate);granulating and disintegrating agents (e.g., cellulose derivativesincluding microcrystalline cellulose, starches including potato starch,croscarmellose sodium, alginates, and alginic acid); binding agents(e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodiumalginate, gelatin, starch, pregelatinized starch, microcrystallinecellulose, magnesium aluminum silicate, carboxymethylcellulose sodium,methylcellulose, hydroxypropyl methylcellulose, ethylcellulose,polyvinylpyrrolidone, and polyethylene glycol); and lubricants,glidants, and antiadhesives (e.g., magnesium stearate, calcium stearate,zinc stearate, sodium stearyl fumurate, sodium lauryl sulfate, stearicacid, silicas, hydrogenated vegetable oils, and talc). Otherpharmaceutically acceptable excipients can be colorants, flavoringagents, plasticizers, humectants, buffering agents, and the like.

Methods of Making Solid Dispersion Systems

The pharmaceutical composition including the solid dispersion (e.g., aspray dried dispersion (SDD) or a hot melt extrusion (HME)) can be madeusing any useful method. Generally, one or more matrix polymers andcompound 1, compound 2, or a salt thereof, are combined either with orwithout a solvent (e.g., one or more of dimethyl acetamide, dimethylformamide, pyrrolidone, methylpyrrolidone, methanol, ethanol, andacetone) to form a mixture (e.g., a liquid mixture) or a solution.Optionally, the matrix polymer and compound 1 or compound 2, either withor without additional excipients, can be heated near or past the glasstransition temperature T_(g) or melting temperature T_(m) to form aliquid mixture. Then, the resultant solution can be spray dried to forma solid dispersion. Alternatively, the method includes a hot-meltextrusion process, where the mixture is heated to form a homogenousmolten mass, extruded, and cooled to form a solid dispersion. Theextrudates can optionally be pelletized or milled to form a soliddispersion amenable for further processing in a suitable unit dosageform.

Finally, the solid dispersion is used for filling any one of the unitdosage forms described herein (e.g., a capsule) or for tabletting. Thesolid dispersion can optionally be further processed before filling ortabletting. Exemplary further processing includes spheronizing,pelletizing, milling, injection molding, sieving, and/or calendaring thesolid dispersion.

Spray Dried Processes

The compositions of the invention can be prepared by any useful process,such as spray drying to form a spray dried dispersion (SDD). In oneexample, one or more matrix polymers and compound 1 or compound 2 arecombined with one or more solvents (e.g., acetone) to form a solutionhaving about 4% (w/w) to about 15% (w/w) of total solids. Percentage(w/w) total solids is determined by dividing the total mass of thecompound and one or more matrix polymers by the total mass of thecompound, one or more matrix polymers, and one or more solvents. Thesolution can then be spray dried to form a SDD, which can optionally befurther drying steps. In particular embodiments, the SDD includes about20% (w/w) of compound 1 or compound 2 with the one or more matrixpolymers (i.e., the weight ratio of compound 1 or compound 2 to thematrix polymer is about 1:4).

For example, to produce a 20% (w/w) compound 1 in a SDD, a solution wasprepared having about 2% (w/w) compound 1 and about 8% (w/w) of apharmaceutically acceptable matrix polymer or a combination of apharmaceutically acceptable matrix polymer in acetone. The solution wasthen spray dried at the appropriate temperature (e.g., between about 95°C. and 110° C. for HPMCAS at the appropriate solution flow rate).

Exemplary matrix polymers for SDD include a cellulose derivative, suchas HPMCAS, e.g., type MG or MF, or CAP; and a polyvinyl acetate, such asPVAP.

The resultant SDD can be blended with one or more excipients, asdescribed herein, and then granulated and/or compacted to produce afinal blend for encapsulating or tabletting. In particular embodiments,the one or more excipients include a binding agent, a filler, adisintegrating agent, a wetting agent, a glidant, and a lubricant.

Hot Melt Extrusion Processes

In some embodiments, the compositions of the invention are prepared byhot melt extrusion (HME). In one example, one or more matrix polymersand compound 1 or compound 2 are combined to form a mixture, where thismixture can optionally include a surfactant. The mixture can then be fedinto a pre-heated extruder (e.g., an extruder having temperature zonesbetween about 75° C. to about 145° C.) to produce an initial extrudate.The extrudate is then pelletized and milled (e.g., to a size less thanabout 500 μm) to produce a fine milled extrudate.

For example, to produce a 20% (w/w) compound 1 extrudate, a pre-blendwas prepared having 20% (w/w) compound 1 and 80% (w/w) of apharmaceutically acceptable matrix polymer or a combination of apharmaceutically acceptable matrix polymer with a surfactant (e.g., anypharmaceutically acceptable matrix polymer and/or surfactant describedherein, e.g., a combination of 75% (w/w) HPMCAS-MF with 5% (w/w) vitaminE TPGS). Any component of the pre-blend can be pre-milled or pre-sieved.For example, the pharmaceutically acceptable matrix polymer and/orsurfactant can be milled through a bar rotor and rasping screen toreduce particle size (e.g., reduce down to ≦600 microns); and/orcompound 1 can be pre-sieved. Then, the pre-blend was processed using aco-rotating twin screw extruder, and the resultant extrudate wasprocessed further by milling (pelletizing) to reduce its particle size(e.g., ≦500 microns). The milled/pelletized extrudate was sieved andblended with various pharmaceutically acceptable excipients (e.g., anydescribed herein), where the resultant blend was then co-milled. Theco-milled blend can be further processed by adding a lubricant (e.g.,magnesium stearate), and the resultant, processed blend can be used tofill a unit dosage form (e.g., a capsule).

Matrix polymers for hot melt extrusion include a cellulose derivative,such as HPMCAS, e.g., type MG or MF; a polyvinyl pyrrolidone (PVP), suchas povidone having a molecular weight of about 50,000 (Kollidon®30,weight-average molecular weight between 44,000 to 54,000); a polyvinylacetate; or a copolymer of a polyvinyl pyrrolidone and a polyvinylacetate (PVP-VA), such as those having a 60:40 ratio ofN-vinyl-2-pyrrolidone to vinyl acetate (copovidone, also available asKollidon® VA 64) and a 20:80 ratio of N-vinyl-2-pyrrolidone to vinylacetate (Kollidon® SR).

In particular embodiments, any surfactant or wetting agent describedherein can be included in the mixture to enhance dissolution and/orenhance stability. An exemplary surfactant includes a pegylated vitaminE compound, such as any described herein (e.g., D-alpha-tocopheryl PEG1000 succinate), in a useful amount (e.g., from about 3% to about 10%(w/w), e.g., about 5% (w/w)).

The resultant extrudate can be blended with one or more excipients, asdescribed herein, and then milled, blended, granulated and/or compactedto produce a final blend for encapsulating or tabletting. In particularembodiments, the one or more excipients include a binding agent, afiller, a surfactant (e.g., a pegylated vitamin E compound), adisintegrating agent, a wetting agent, a glidant, and a lubricant.

Dosage and Administration

For administration to animal or human subjects, the dosage of compound1, compound 2, or a salt thereof, is typically 0.1 to 15 mg/kg, morepreferably 3 to 5 mg/kg. However, dosage levels can be highly dependenton the nature of the condition, drug efficacy, the condition of thepatient, the judgment of the practitioner, and the frequency and mode ofadministration.

Compound 1, compound 2, or a salt thereof, is preferably provided in atherapeutically effective amount, which may be, for example, a dailyamount of from 25 mg to 1,600 mg, more preferably 40 mg to 800 mg, andeven more preferably 80 mg to 320 mg. In one embodiment, apharmaceutical composition comprising a compound 1, compound 2, or asalt thereof, comprises a capsule, for example in unit dosage formhaving from 20 mg to 250 mg of compound 1, compound 2, or a saltthereof, (e.g., from 20 mg to 250 mg, such as from 20 mg to 30 mg, from20 mg to 40 mg, from 20 mg to 50 mg, from 20 mg to 75 mg, from 20 mg to100 mg, from 20 mg to 125 mg, from 20 mg to 150 mg, from 20 mg to 175mg, from 20 mg to 200 mg, from 20 mg to 225 mg, from 30 mg to 40 mg,from 30 mg to 50 mg, from 30 mg to 75 mg, from 30 mg to 100 mg, from 30mg to 125 mg, from 30 mg to 150 mg, from 30 mg to 175 mg, from 30 mg to200 mg, from 30 mg to 225 mg, from 30 mg to 250 mg, from 40 mg to 50 mg,from 40 mg to 75 mg, from 40 mg to 100 mg, from 40 mg to 125 mg, from 40mg to 150 mg, from 40 mg to 175 mg, from 40 mg to 200 mg, from 40 mg to225 mg, from 40 mg to 250 mg, from 50 mg to 75 mg, from 50 mg to 100 mg,from 50 mg to 125 mg, from 50 mg to 150 mg, from 50 mg to 175 mg, from50 mg to 200 mg, from 50 mg to 225 mg, from 50 mg to 250 mg, from 60 mgto 75 mg, from 60 mg to 100 mg, from 60 mg to 125 mg, from 60 mg to 150mg, from 60 mg to 175 mg, from 60 mg to 200 mg, from 60 mg to 225 mg,from 60 mg to 250 mg, from 70 mg to 75 mg, from 70 mg to 100 mg, from 70mg to 125 mg, from 70 mg to 150 mg, from 70 mg to 175 mg, from 70 mg to200 mg, from 70 mg to 225 mg, from 70 mg to 250 mg, from 80 mg to 100mg, from 80 mg to 125 mg, from 80 mg to 150 mg, from 80 mg to 175 mg,from 80 mg to 200 mg, from 80 mg to 225 mg, from 80 mg to 250 mg, from90 mg to 100 mg, from 90 mg to 125 mg, from 90 mg to 150 mg, from 90 mgto 175 mg, from 90 mg to 200 mg, from 90 mg to 225 mg, from 90 mg to 250mg, from 100 mg to 125 mg, from 100 mg to 150 mg, from 100 mg to 175 mg,from 100 mg to 200 mg, from 100 mg to 225 mg, and from 100 mg to 250mg). These unit dosage forms can be administered to achieve any dailyamount described herein, such as by administering one to five timesdaily (e.g., one, two, three, four, or five times daily).

Unit Dosage Forms

For use as treatment of human and animal subjects, compound 1, compound2, or a salt thereof, can be formulated as pharmaceutical or veterinarycompositions. Depending on the subject to be treated, the mode ofadministration, and the type of treatment desired (e.g., prevention,prophylaxis, or therapy) the compounds are formulated in ways consonantwith these parameters. A summary of such techniques is found inRemington: The Science and Practice of Pharmacy, 21st Edition,Lippincott Williams & Wilkins, (2005); and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, each of which is incorporated hereinby reference.

Compound 1, compound 2, or a salt thereof, may be present in amountstotaling 1-95% by weight of the total weight of the composition. Thecomposition including compound 1, compound 2, or a salt thereof, and apharmaceutically acceptable matrix polymer may be provided in a dosageform that is suitable for oral administration. Alternatively, the unitdosage form of the invention includes substantially amorphous compound1, compound 2, or a salt thereof, and a pharmaceutically acceptableexcipient (e.g., fillers, diluents, lubricants, and/or glidants). Thus,the pharmaceutical composition may be in the form of, e.g., hardcapsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), soft gelatin capsules, tablets, caplets,enteric coated tablets, chewable tablets, enteric coated hard gelatincapsules, enteric coated soft gelatin capsules, minicapsules, lozenges,films, strips, gelcaps, dragees, suspensions, syrups, or sprinkles. Thecompositions may be formulated according to conventional pharmaceuticalpractice.

In particular embodiments, compound 1, compound 2, or a salt thereof,and a matrix polymer are included in a capsule or compressed into atablet. Compound 1, compound 2, or a salt thereof, in combination with amatrix polymer can be in any form, such as a semi-solid suspension, asolid suspension, a homogenous melt, solid particles, or semi-solidparticles. The form of the compound 1, compound 2, or a salt thereof,can be determined based on dose. For example, a capsule filled with asolid dispersion can be used for approximately 10-50% drug loading.

Exemplary unit dosage forms are hard capsules (e.g., hard gelatincapsules or hard hydroxypropyl methylcellulose capsules) and softgelatin capsules. When soft gelatin capsules are used, it is preferredthat when a composition contains a polyethylene glycol, the compositionof the soft gelatin capsule shell contains a humectant, for example,sorbitol, to prevent brittleness of the soft gelatin capsule.

Utility and Treatment of Conditions

Conditions that can be treated using the compositions or formulationsdescribed herein include pain (e.g., chronic or acute pain), epilepsy,Alzheimer's disease, Parkinson's disease, diabetes, cancer, sleepdisorders, obesity, mood disorders, psychosis such as schizophrenia,tinnitus, amyotrophic lateral sclerosis, glaucoma, ischaemia, spasticitydisorders, obsessive compulsive disorder, restless leg syndrome,Tourette syndrome, overactive bladder, renal disease, neuroprotection,and addiction. For example, the condition can be pain (e.g., neuropathicpain or post-surgery pain), epilepsy, migraine, Parkinson's disease,depression, schizophrenia, psychosis, or tinnitus.

Epilepsy as used herein includes but is not limited to partial seizuressuch as temporal lobe epilepsy, absence seizures, generalized seizures,and tonic/clonic seizures.

Cancer as used herein includes but is not limited to breast carcinoma,neuroblastoma, retinoblastoma, glioma, prostate carcinoma, esophagealcarcinoma, fibrosarcoma, colorectal carcinoma, pheochromocytoma,adenocarcinoma, insulinoma, lung carcinoma, melanoma, and ovariancancer.

Acute pain as used herein includes but is not limited to nociceptivepain and post-operative pain. Chronic pain includes, but is not limitedto, neuropathic pain, peripheral neuropathic pain such as post-herpeticneuralgia, diabetic neuropathic pain, neuropathic cancer pain,HIV-associated neuropathy, erythromelalgia, failed back-surgerysyndrome, trigeminal neuralgia, and phantom limb pain; centralneuropathic pain such as multiple sclerosis related pain, Parkinsondisease related pain, post-stroke pain, post-traumatic spinal cordinjury pain, lumbosacral radiculopathy, cervical radiculopathy, brachialradiculopathy, and pain in dementia; musculoskeletal pain such asosteoarthritic pain and fibromyalgia syndrome; inflammatory pain such asrheumatoid arthritis, juvenile idiopathic arthritis, ankylosingspondylitis, psoriatic arthritis, inflammatory bowel disease, primarydysmenorrhea, and endometriosis; headache such as migraine, clusterheadache, tension headache syndrome, facial pain, and headache caused byother diseases; visceral pain such as interstitial cystitis, irritablebowel syndrome, and chronic pelvic pain syndrome; and mixed pain such aslower back pain, neck and shoulder pain, burning mouth syndrome, andcomplex regional pain syndrome.

In treating osteoarthritic pain, joint mobility can also improve as theunderlying chronic pain is reduced. Thus, use of compositions andformulations of the present invention to treat osteoarthritic painincludes use of such compositions or formulations to improve jointmobility in patients suffering from osteoarthritis or other conditionpresenting with decreased joint mobility.

The compositions and formulations described herein can be tested forefficacy in any standard animal model of pain. Various models test thesensitivity of normal animals to intense or noxious stimuli(physiological or nociceptive pain). These tests include responses tothermal, mechanical, or chemical stimuli. Thermal stimuli usuallyinvolve the application of hot stimuli (typically varying between 42-55°C.) including, for example: radiant heat to the tail (the tail flicktest), radiant heat to the plantar surface of the hindpaw (theHargreaves test), the hotplate test, and immersion of the hindpaw ortail into hot water. Immersion in cold water, acetone evaporation, orcold plate tests may also be used to test cold pain responsiveness.Tests involving mechanical stimuli typically measure the threshold foreliciting a withdrawal reflex of the hindpaw to graded strengthmonofilament von Frey hairs or to a sustained pressure stimulus to a paw(e.g., the Ugo Basile analgesiometer). The duration of a response to astandard pinprick may also be measured. When using a chemical stimulus,the response to the application or injection of a chemical irritant(e.g., capsaicin, mustard oil, bradykinin, ATP, formalin, or aceticacid) to the skin, muscle joints, or internal organs (e.g., bladder orperitoneum) is measured.

In addition, various tests assess pain sensitization by measuringchanges in the excitability of the peripheral or central components ofthe pain neural pathway. In this regard, peripheral sensitization (i.e.,changes in the threshold and responsiveness of high thresholdnociceptors) can be induced by repeated heat stimuli as well as theapplication or injection of sensitizing chemicals (e.g., prostaglandins,bradykinin, histamine, serotonin, capsaicin, or mustard oil). Centralsensitization (i.e., changes in the excitability of neurons in thecentral nervous system induced by activity in peripheral pain fibers)can be induced by noxious stimuli (e.g., heat), chemical stimuli (e.g.,injection or application of chemical irritants), or electricalactivation of sensory fibers.

Various pain tests developed to measure the effect of peripheralinflammation on pain sensitivity can also be used to study the efficacyof the compositions (Stein et al., Pharmacol. Biochem. Behay. 31:445-451, 1988; Woolf et al., Neurosci. 62:327-331, 1994). Additionally,various tests assess peripheral neuropathic pain using lesions of theperipheral nervous system. One such example is the “axotomy pain model”(Watson, J. Physiol. 231:41, 1973). Other similar tests include the SNLtest which involves the ligation of a spinal segmental nerve (Kim andChung, Pain 50: 355, 1992), the Seltzer model involving partial nerveinjury (Seltzer, Pain 43: 205-18, 1990), the spared nerve injury (SNI)model (Decosterd and Woolf, Pain 87:149, 2000), chronic constrictioninjury (CCl) model (Bennett, Muscle Nerve 16:1040, 1993), testsinvolving toxic neuropathies such as diabetes (streptozocin model),pyridoxine neuropathy, taxol, vincristine, and other antineoplasticagent-induced neuropathies, tests involving ischemia to a nerve,peripheral neuritis models (e.g., CFA applied peri-neurally), models ofpost-herpetic neuralgia using HSV infection, and compression models.

In all of the above tests, outcome measures may be assessed, forexample, according to behavior, electrophysiology, neurochemistry, orimaging techniques to detect changes in neural activity.

EXAMPLES Example 1 In Vitro Absorption of Compound 1

Absorption of particular drugs may be limited by biological factors,such as reduced cellular permeability in the intestine. Many cellularmechanisms can influence permeability, such as reduced passiveparacellular and transcellular transport or increased active export bythe efflux transporter protein P-glycoprotein. Thus, the use ofself-emulsifying carriers may not be beneficial for drugs having limitedcellular permeability, where methods to increase the solubilization of adrug may not increase its permeability in the gastrointestinal tract.Experiments were conducted to assess the apparent intestinalpermeability of compound 1 using a Caco-2 cell model. Overall, the dataherein suggest that compound 1 is not limited by permeability in theintestine, and formulations that promote delivery of compound 1 to thegastrointestinal tract may reduce food effects or increasebioavailability.

Briefly, Caco-2 cells were used as an in vitro model for predictingabsorption through the intestinal epithelium. Confluent monolayers ofCaco-2 cells were grown on collagen-coated, microporous, polycarbonatemembranes (12-well Costar Transwell® plates) that are placed between twochambers. The apical side of the monolayer was exposed to the buffersolution in a first chamber, but the basolateral side of the monolayeradhered to microporous membranes fluidically connected to a secondchamber. The dosing solution was added to the first chamber formeasurements in the apical-to-basolateral direction (A-to-B) and to thesecond chamber for measurements in the basolateral-to-apical direction(B-to-A). Accordingly, for A-to-B measurements, the first chamber wasthe receiver chamber and the second chamber was the donor chamber; forB-to-A measurements, the first chamber was the donor chamber and thesecond chamber was the receiver chamber. The permeability assay bufferwas Hanks Balanced Salt Solution containing 10 mM HEPES and 15 mMglucose at a pH of 7.4. The buffer in the receiver chamber alsocontained 1% bovine serum albumin. The dosing solution concentration was1 μM of compound 1 in the assay buffer. All donor chambers were firstpre-incubated for five minutes with dosing solution to attempt tosaturate any non-specific binding sites on the device with testcompound. After five minutes, the solution was removed and replaced withfresh dosing solution, and time was recorded as 0. Cell monolayers weredosed on the apical side/first chamber (for A-to-B measurements) orbasolateral side/second chamber (for B-to-A measurements) and incubatedat 37° C. with 5% CO₂ in a humidified incubator. At 30 and 60 minutes,aliquots were taken from the receiver chambers and replaced with freshassay buffer. Samples were taken from the donor chamber at 0 and 60minutes. Each experiment was performed in triplicate.

The apparent permeability (P_(app)), percent recovery, and efflux ratiowere calculated as follows:

${{P_{app}\left\lbrack {{cm}\mspace{14mu} s^{- 1}} \right\rbrack} = {\frac{C_{r}}{t} \times \frac{V_{r}}{A \times C_{0}}}},{{{Percent}\mspace{14mu} {{recovery}\mspace{14mu}\lbrack\%\rbrack}} = {100 \times \frac{\left( {V_{r} \times C_{r,{final}}} \right) + \left( {V_{d} \times C_{d,{final}}} \right)}{V_{d} \times C_{N}}}},{and}$${{{Efflux}\mspace{14mu} {ratio}} = \frac{P_{app}\left( {B\text{-}{to}\text{-}A} \right)}{P_{app}\left( {A\text{-}{to}\text{-}B} \right)}},$

where

$\frac{{Cr}}{t}\left\lbrack {µ\; M\mspace{14mu} s^{- 1}} \right\rbrack$

is the slope of the cumulative concentration in the receiver chamber asa function of time; V_(r) [cm³] is the volume of the receiver chamber;V_(d) [cm³] is the volume of the donor chamber; A [cm²] is the area ofthe cell monolayer, which is estimated to be about 1.13 cm² for the12-well Costar Transwell® plates; C₀ [μM] is the measured concentrationin the donor chamber at t=0 hours; C_(N) [μM] is the nominalconcentration of the dosing solution; C_(r final) [μM] is the cumulativeconcentration in the receiver chamber at the end of the incubationperiod; and C_(d final) [μM] is the cumulative concentration in thedonor chamber at the end of the incubation period.

Table 2 shows the apparent permeability for the apical-to-basolateraldirection (A-to-B), the basolateral-to-apical direction (B-to-A), andcell-free condition. Compound 1 was classified as having a highpermeability coefficient, due to an apparent permeability valueP_(app)(A-to-B) more than 1.0×10⁻⁶ cm/s. Efflux of compound 1 was notconsidered significant, due to an efflux ratio of less than 3. Thus,absorption of compound 1 in humans is not expected to be permeabilitylimited.

TABLE 2 Percent Efflux Ratio Initial Donor Recovery P_(app) (10⁻⁶ cm/s)(P_(app)(B-to-A)/P_(app) Direction Conc. (μM) (%) R1 R2 R3 Avg.(A-to-B)) A-to-B 0.69 28 4.37 4.31 6.78 5.15 0.8 B-to-A 0.59 37 5.043.48 4.45 4.32 Cell-free 0.68 54 1.71 2.21 1.69 1.87

Example 2 Solubility of Solid Dispersion Formulations in Gastric andIntestinal Media

Eight solid dispersion formulations were tested at 20% (w/w) loading ofcompound 1. As shown in FIG. 1A, unformulated compound 1 rapidlyprecipitated from the FaSSIF media following exposure to gastric media.

Various formulations were tested to reduce precipitation. As shown inFIGS. 1A-1H, solubility was measured for the following formulations:carboxymethylethyl cellulose (CMEC, FIG. 1A), cellulose acetatephthalate (CAP, FIG. 1B), hydroxypropylmethyl cellulose acetatesuccinate M grade (HPMCAS-M, FIG. 1C), polyvinyl acetate phthalate(PVAP, FIG. 1D), methacrylic acid-methyl methacrylate copolymer(Eudragit® L 100, FIG. 1E), polyethyleneglycol-polyvinylcaprolactam-polyvinylacetate copolymer (Soluplus®, FIG.1F), hydroxypropylmethyl cellulose phthalate (HPMCP-H55, FIG. 1G), andpolyvinylpyrrolidone vinylacetate copolymer (PVP-VA, FIG. 1H). Atapproximately 13 minutes, the media was transferred from gastric media(pH of 1.0) to Fasted State Simulated Intestinal Fluid media (FaSSIFmedia, pH of 6.5).

In all instances, the solid dispersion formulations providedimprovements in solubility of compound 1. Dispersions having the highestC_(max) included CMEC, CAP, HPMCAS-M, PVAP, and Eudragit® L 100 (FIGS.1A-1E). Among these, PVAP had the fastest precipitation rate, andHPMCAS-M and Eudragit® L 100 had the slowest dissolution rates.

Further tests were conducted with different % loading of compound 1.Dissolution rates were measured for formulations have 35% (w/w) loading(FIGS. 2A-2C) and 50% (w/w) loading (FIGS. 3A-3D). CAP, HPMCAS-M,Eudragit® L 100, and PVAP were further analyzed for these tests.Generally, increased % loading exhibited lower free drug concentrationsin the media (shown as open circles). Without wishing to be limited bytheory, as % loading increases, the amount of matrix polymer needed toinhibit precipitation of compound 1 also increases. Overall, dissolutionrates for 35% and 50% loading were comparable to those for 20% loadingof the same polymers, and PVAP provided the highest C_(max) and the mostrapid precipitation.

Physiological-based pharmacokinetic (PBPK) modeling (GastroPlus® v.6.1)was conducted to predict the in vivo fraction absorbed and thefed-fasted ratio at 10 mg/kg and 100 mg/kg doses. These predictiveestimates are provided for fraction absorbed (FIG. 4A) and fed-fastedratio (FIG. 4B) for 20%, 35%, and 50% (w/w) loading of compound 1. Thesedata suggest enhanced absorption and reduced fed-fasted ratio for arange of formulations at 20% and 35% loading of compound 1.

Example 3 Solubility of Formulations 1 and 2

Based on the dissolution data provided herein, formulations for 20%(w/w) loading of formula 1 in CAP (formulation 1) and HPMCAS-M(formulation 2) were further tested with media transition times longerthan 13 minutes to better represent human physiological gastric emptyingtimes. At approximately 30 minutes, the media was transferred fromgastric media (pH of 1.0) to Fasted State Simulated Intestinal Fluidmedia (FaSSIF media, pH of 6.5). FIGS. 5A-5B show that formulations 1and 2 performed similarly to experiments performed at shorter times.

Example 4 Physical Characterization of Formulations

Various solid dispersion formulations were tested using modulateddifferential scanning calorimetry (MDSC). MDSC measurements provideglass transition temperature T_(g) values, which can be used tounderstand the molecular mobility of a drug within the dispersion. FIG.6 shows the MDSC traces and T_(g) values for CMEC, HPMCAS-M, CAP, andPVAP formulations having 20% (w/w) loading of compound 1. Data forEudragit® L 100 are not shown, but T_(g) is likely greater than 150° C.due to polymer degradation above this temperature. All recorded T_(g)values were at least twice as high as compound 1 alone (T_(g)=41.6° C.).Lower T_(g) values could indicate potential stability issues over longperiods of time or at an increased temperature or pressure. Table 3provides T_(g) values for CAP (formulation 1), HPMCAS-M (formulation 2),and PVAP.

TABLE 3 Percentage (w/w) T_(g) (° C.) T_(g) (° C.) of compound 1 atambient at 75% Formulation with polymer relative humidity relativehumidity CAP 20 130-132 83 (formulation 1) 35 116 N.D. 50 N.D. N.D.HPMCAS-M 20 88-91 54 (formulation 2) 35 63 N.D. 50 55 N.D. PVAP 20 116N.D. 35 106 N.D. 50 90 N.D. N.D.: not determined

Formulations having CAP and HPMCAS-M were further analyzed using powderX-ray diffraction (PXRD). As shown in FIG. 7, no evidence of crystallinecompound 1 was detected in either formulation 1 or 2.

Example 5 In Vivo Study in Rats

The pharmacokinetics of formulations having 20% (w/w) of compound 1 inmatrix polymer were studied in rats. Table 4 provides a summary of theresults for this in vivo study. Formulation 1 is 20% (w/w) of compound 1in CAP. Formulation 2 is 20% (w/w) compound 1 in HPMCAS-M. Controlindicates compound 1 in 0.5% Tween® 80 in 0.5% carboxy methylcellulose(CMC). Doses included 10 to 100 mg of compound 1 to kg of the subject(mg/kg).

TABLE 4 C_(max) T_(max) t_(1/2) AUC_(∞) AUC_(0-last) (ng/mL, (hr, (hr,(h * mg/mL, (h * mg/mL, Dose Formulation mean) mean) mean) mean) mean) 10 mg/kg Control 89 3.33 1.54 503 466 dose 1 (CAP) 82.0 6.67 1.99 540385 2 (HPMCAS-M) 157 4.67 2.15 914 732  30 mg/kg Control 152 3.33 4.071262 831 dose 1 (CAP) 392 3.33 2.07 2215 1925 2 (HPMCAS-M) 417 3.00 4.183970 2449 100 mg/kg Control 450 5.33 3.22 3461 2155 dose 1 (CAP) 5912.67 4.06 5179 3807 2 (HPMCAS-M) 714 3.00 2.64 4628 3667

Data for each animal are provided for formulation 1 (Table 5 and FIG.8A), formulation 2 (Table 6 and FIG. 8B), and control (Table 7 and FIG.8C) for three doses. FIGS. 9A-9C provides data for these formulationsfor each dose. Overall, both formulations 1 and 2 showed enhanced oralbioavailability of compound 1, compared to control.

TABLE 5 Dose of Form- ulation 1 (CAP) Pharmacokinetic parameters (20%C_(max) T_(max) t_(1/2) AUC_(∞) AUC_(0-last) (w/w)) Animal (ng/mL) (hr)(hr) (h * ng/mL) (h * ng/mL)  10 mg/kg 10 70.8 8.00 NC NC 336 11 72.16.00 1.75 451 369 12 103 6.00 2.23 629 451 Mean 82.0 6.67 1.99 540 385SD 18.2 1.15 0.341 126 59.5 SEM 10.5 0.667 0.241 89.1 34.4  30 mg/kg 13361 2.00 1.74 1912 1778 14 492 4.00 1.18 2191 2111 15 324 4.00 3.28 25421885 Mean 392 3.33 2.07 2215 1925 SD 88.3 1.15 1.08 316 170 SEM 51.00.667 0.626 182 97.9 100 mg/kg 16 661 2.00 4.06 5179 3633 17 540 4.00 NCNC 3709 18 572 2.00 NC NC 4080 Mean 591 2.67 4.06 5179 3807 SD 62.7 1.15n/a n/a 239 SEM 36.2 0.667 n/a n/a 138

TABLE 6 Dose of Formulation 2 Pharmacokinetic parameters (HPMCAS-M)C_(max) T_(max) t_(1/2) AUC_(∞) AUC_(0-last) (20% (w/w)) Animal (ng/mL)(hr) (hr) (h * ng/mL) (h * ng/mL) 10 mg/kg 19 119 6.00 2.09 690 505 20174 2.00 2.25 845 762 21 178 6.00 2.10 1206 928 Mean 157 4.67 2.15 914732 SD 33.0 2.31 0.0868 265 213 SEM 19.0 1.33 0.0501 153 123 30 mg/kg 22342 1.00 2.10 2068 1845 23 468 4.00 8.15 6620 2706 24 440 4.00 2.27 32222795 Mean 417 3.00 4.18 3970 2449 SD 66.2 1.73 3.44 2366 525 SEM 38.21.00 1.99 1366 303 100 mg/kg  25 574 6.00 2.74 5112 3745 26 893 2.002.55 4143 3479 27 674 1.00 NC NC 3778 Mean 714 3.00 2.64 4628 3667 SD163 2.65 0.136 685 164 SEM 94.2 1.53 0.0963 484 94.8

TABLE 7 Pharmacokinetic parameters Dose of C_(max) T_(max) t_(1/2)AUC_(∞) AUC_(0-last) Control Animal (ng/mL) (hr) (hr) (h * ng/mL) (h *ng/mL)  10 mg/kg 1 96.7 6.00 0.858 558 534 2 110 2.00 1.65 559 517 360.6 2.00 2.13 391 346 Mean 89 3.33 1.54 503 466 SD 26 2.3 0.64 97.0 104SEM 15 1.3 0.37 56.0 60.0  30 mg/kg 4 125 2.00 8.28 1888 845 5 169 4.001.34 898 857 6 162 4.00 2.59 998 790 Mean 152 3.33 4.07 1262 831 SD 23.61.15 3.70 545 35.3 SEM 13.7 0.667 2.14 315 20.4 100 mg/kg 7 434 4.002.88 2812 2121 8 361 6.00 2.49 2637 1893 9 554 6.00 4.29 4934 2453 Mean450 5.33 3.22 3461 2155 SD 97.4 1.15 0.945 1279 282 SEM 56.3 0.667 0.545738 163

Example 6 In Vivo Study in Dogs

The pharmacokinetics of formulations 1 and 2 were studied in dogs usinga dosage of 10 mg/kg (mg of compound 1/kg of subject). Table 8 providesa summary of the results for this in vivo study. Control indicatescompound 1HCl in 0.5% Tween 80 in 0.5% CMC. FIG. 10 shows enhanced oralbioavailability for formulations 1 and 2.

TABLE 8 T_(max) t_(1/2) C_(max) AUC_(0-last) AUC₀₋₂₄ AUC_(∞) Animal Rsq(hr) (hr) (ng/mL) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL) Group 1 1311019NC 1 NC   14.4    7.82   15.0 NC (control) 1311108 0.03 2 NR 111 470 470NR 1457366 NC 1 NC   17.3 131 131 NC Mean 0.03   1.3 NC   47.6 203 205NC SD NA   0.6 NA  55 239 236 NA Group 2 1376382 0.99 1 8.9 603 1740 1740  1820 (formulation 2 1401603 0.25 1 NR 160 800 800 NR (HPMCAS-M))1408951 0.96 2 12.8  300 1230  1230  1480 Mean 0.73   1.3 10.9  3541260  1260  1650 SD 0.41   0.6 NA 226 472 472 NA Group 3 1296265 0.88 11.5 169 384 399  400 (formulation 1 1502906 0.14 2 NR 135 600 600 NR(CAP)) 5955823 0.43 1 NR 254 1330  1330  NR Mean 0.48   1.3 1.5 186 773777  400 SD 0.37   0.6 NA   61.3 498 492 NA NC = Not calculated byWinNonlin due to insufficient data points for elimination phase. NR =Not reported, due to poor goodness-of-fit (R² < 0.8) for eliminationphase.

In Table 8 above, the AUC₀₋₂₄ was about six times greater for Group 2(HPMCAS) and more than three times greater for Group 3 (CAP), ascompared to Group 1 (control).

Example 7 Phase 1 (part 1) Study in Healthy Human Subjects

The pharmacokinetics of a spray dried dispersion (SDD) formulationhaving HPMCAS were studied in healthy, human subjects using an oraldosage of 225 mg of compound 1 (three 75-mg capsules).

Compound 1 (free base) was supplied in #00 white opaque hard gelatinshell capsules. Each capsule contained 75 mg of compound 1 (free base)in hypromellose acetate succinate (HPMCAS-MG) as a spray drieddispersion, which was dry blended with lactose, microcrystallinecellulose, sodium lauryl sulphate, colloidal silicon dioxide,croscarmellose sodium, and magnesium stearate. The spray drieddispersion was prepared by using a solution of compound 1 withhypromellose acetate succinate, grade MG (HPMCAS-MG), with acetone asthe spray drying solvent. The quantitative composition of these SDDcapsules is shown in Table 9.

TABLE 9 Quantity per Component Function Standard Capsule (mg) compound 1(free base) API C of A 75.00 Hypromellose acetate Polymer component ofPh. Eur., NF, JP 300.00 succinate Type MG the solid dispersion Lactosemonohydrate Binder-Filler Ph. Eur., NF, JP 38.24 Microcrystallinecellulose Binder-Filler Ph. Eur., NF, JP 78.24 Croscarmellose sodiumDisintegrant Ph. Eur., NF, JP 17.00 Sodium lauryl sulphate Wetting agentPh. Eur., NF, JP 4.24 Colloidal silicon dioxide Flow aid/Glidant NF 2.14Magnesium stearate Lubricant Ph. Eur., NF, JP 2.14 Capsule Shell, hardgelatin Dosage form na white opaque size 00 Total Fill Weight: 517.0Abbreviations: API = Active Pharmaceutical Ingredient; C ofA—Certificate of Analysis; Ph. Eur. = European Pharmacopoeia; NF =National Formulary; JP = Japanese Pharmacopeia

This single-center, open-label, crossover design study was conducted todetermine the relative bioavailability, safety, and tolerability of theoral, SDD formulation under fasted and fed conditions in healthysubjects. The study comprised of an up to 21-day screening period, two4-day inpatient clinic stays, and 35-days outpatient follow-up period.Sixteen subjects were randomized to the fed state or fasted state.

On Day 1 in Period 1, subjects received capsules either in the fastedstate (defined as no food consumption for 10 hours and no water for 2hours prior to oral dosing) or the fed state (defined as consumption ofa high-fat meal 30 minutes prior to oral dosing and must completelyconsume the meal before taking the capsules). Subjects were administered225 mg of compound 1 in capsules. Immediately prior to dosing, vitalsigns were measured, a 12-lead ECG was obtained, and a pharmacokinetics(PK) blood sample was obtained. Subjects were then administered 225 mgof compound 1. Blood samples for PK determinations were obtained at 0.5,1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 16 hourspost-oral dose; vital signs and 12-lead ECGs were obtained at 3, 4, and5 hours post-dose; and any concomitant medications and adverse events(AE) were recorded.

During Days 1-4 (inpatient period) and Days 5-6 (outpatient period) inPeriod 1, blood samples for PK determinations, vital signs, and 12-leadECGs were obtained at various time points; and adverse events (AE) wererecorded. In particular, blood samples for PK determinations wereobtained at 24 and 36 hours post-dose on Period 1/Day 2, at 48 and 60hours post-dose on Period 1/Day 3, and at 72 hours post-dose on Period1/Day 4. After completion of all of the Period 1/Day 4 assessments, thesubjects were discharged from the clinical testing facility. Subjectsreported back to the clinical testing facility on the mornings of Period1/Days 5 and 6 for collection of PK blood samples at 96 hours (Period1/Day 5) and 120 hours (Period 1/Day 6) post-dose.

After a one week washout period, subjects who received capsules in thefed state in Period 1 then received capsules in the fasted state inPeriod 2 (defined as no food consumption for 10 hours and no water for 2hours preceding oral dosing); and subjects who received capsules in thefasted state in Period 1 received capsules in the fed state in Period 2.

A PK blood sample was taken at 168 hours after the first oral dose ofstudy drug in Period 1; this sample, which was drawn immediately beforethe subject takes the 225-mg oral dose on the morning of Period 2/Day 1,was used as the pre-dose sample for Period 2. After collection of thepre-dose PK blood sample, subjects took a single oral dose of 225 mg ofcompound 1 (free base). Blood samples for PK determinations wereobtained at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and16 hours post-oral dose; vital signs and 12-lead ECGs were obtained at3, 4, and 5 hours post-oral dose; and any concomitant medications andAEs were recorded.

During Days 1-4 (inpatient period) in Period 2, blood samples for PKdeterminations, vital signs, and 12-lead ECGs were obtained at varioustime points; and adverse events (AE) were recorded. In particular, bloodsamples for PK determinations were obtained at 24 and 36 hours post-oraldose on Period 2/Day 2, at 48 and 60 hours post-dose on Period 2/Day 3,and at 72 hours post-oral dose on Period 2/Day 4. After completion ofall of the Period 2/Day 4 assessments, the subjects were discharged fromthe clinical testing facility. Subjects returned to the clinical testingfacility in the fasted state for an end of study (EOS) visit on Period2/Day 36 or at the time of premature termination from the study. Afasting blood sample for PK determinations (840 hours post-oral dosing)and fasting blood and urine samples for safety laboratory determinationswere obtained, vital signs were measured, and a physical examination wasperformed. A pregnancy test (β-hCG) was performed for female subjects.

For the data in Table 10, PK blood samples were collected to 168 hoursfor Period 1 and to 840 hours for Period 2. Table 10 shows the effect ofPeriod 1 versus Period 2 on the estimation of terminal half-life.

TABLE 10 Half-Life (hr) Subject Period 1 Period 2 Ratio 3001 130 316 41%3002 99 306 32% 3003 199 296 67% 3004 126 178 71% 3005 72 388 19% 3006129 493 26% 3007 265 220 121%  3008 115 357 32% 3009 100 309 33% 3010 98186 53% 3011 111 282 39% 3012 122 402 30% 3013 79 231 34% 3014 86 20741% 3015 97 377 26% 3016 116 370 31% Mean 122 307 40% CV % 40% 29% 138% 

For the data in Table 11, corrected AUC_(0-∞), C_(max), and T_(max)values are provided for all samples in Period 1 and in Period 2. Table11 shows the effect of food on the time to reach maximum concentration(T_(max)), as well as AUC_(0-∞) and C_(max) values that have beencorrected for carry-over effect and the truncated observation period ofPeriod 2. Carry-over effects were observed in Period 2, likely due toincomplete washout.

TABLE 11* AUC_(0-∞) C_(max) T_(max) (hr * ng/mL) (ng/mL) (hr) FastedFasted Fed − Subject Fasted Fed Fed Fasted Fed Fed Fasted Fed Fasted3001 5019 5298 95% 528 608 87% 1.3 5.0 3.7 3002 5544 10031 55% 916 649141% 2.5 5.0 2.5 3003 7399 11462 65% 431 519 83% 10.0 6.0 −4.0 3004 62967591 83% 685 823 83% 2.0 4.0 2.0 3005 6841 14742 46% 806 1054  76% 5.05.0 0.0 3006 5161 4381 118%  563 328 172% 2.5 8.0 5.5 3007 6210 8572 72%250 915 27% 4.0 5.0 1.0 3008 2634 7282 36% 423 591 72% 1.8 6.0 4.2 30094099 8667 47% 530 806 66% 3.0 6.0 3.0 3010 5854 6730 87% 473 449 105%1.3 6.0 4.7 3011 3432 8157 42% 372 882 42% 3.0 5.0 2.0 3012 4287 441997% 595 613 97% 1.5 5.0 3.5 3013 3604 7244 50% 556 570 98% 3.0 4.0 1.03014 4110 5884 70% 719 787 91% 1.5 6.0 4.5 3015 4180 10551 40% 425 92046% 3.0 5.0 2.0 3016 5254 6346 83% 576 531 109% 1.8 5.0 3.2 Mean 49927960 68% 553 690 87% 3.0 5.4 2.4 Median n/a n/a n/a n/a n/a n/a 2.5 5.02.8 % CV 27% 34% 36% 30% 29% 41% 0.7 0.2 94% Geometric 4820 7551 65% 529662 80% 2.5 5.3 n/a Mean *AUC and C_(max) values have been corrected forcarry-over effect.

In Table 11 above, the ratio of mean AUC_(0-∞), C_(max) , and T_(max)are 1.59, 1.25, and 1.8, respectively, for fed subjects to fastedsubjects. Furthermore, administration of the SDD formulation produced acoefficient of variation in AUC_(0-∞), and C_(max) of less than 35% infasted subjects (i.e., 27% and 30%, respectively) and in fed subjects(i.e., 34% and 29%, respectively). Finally, administration of the SDDcomposition to fed and fasted subjects produced a coefficient ofvariation in AUC_(∞) of less than 40% (i.e., 36%) and in C_(max) of lessthan 60% (i.e., 41%).

FIGS. 11A-11B show that compound 1 in an SDD formulation (as a freebase) has improved PK properties, compared to a micronized formulation(as an HCl salt). As shown in FIG. 11A, the ratio of these values forfasted versus fed subjects was about three-fold higher for the SDDformulation compared to the micronized formulation. Thus, use of the SDDformulation reduced the food effect of compound 1, as compared to themicronized formulation. Furthermore, the SDD formulation providedimproved AUC values relative to the micronized formulation. As shown inFIG. 11B, the AUC₀₋₂₄ values for the SDD formulation were more than 900%and 150% greater for fasted and fed states, respectively, than that forthe micronized formulation. Additional data comparing SDD and micronizedformulations are provided in Table 12. Overall, both AUC₀₋₂₄ and C_(max)for the SDD formulation were increased, and significant improvementswere observed in intersubject variability (e.g., improved CV) relativeto the micronized formulation.

TABLE 12 AUC₀₋₂₄ C_(max) Mean T_(max) (hr * ng/mL)* (ng/mL)* (hr)*Formulation Fasted Fed Fasted Fed Fasted Fed SDD (free base), 2574  3954553  690 3.0 5.0 225 mg dose^(a) (30%) (27%) (30%) (29%) Micronized 4892311 65 336 3.0 5.0 (HCl salt), (82%) (26%) (94%) (33%) 200 mg dose^(b)Micronized 394 2703 51 389 3.0 7.0 (HCl salt), (42%) (39%) (56%) (35%)400 mg dose^(c) *CV provided in parentheses. ^(a)Data for AUC₀₋₂₄,C_(max), and T_(max) for SDD are corrected for the carry-over effect andtruncated Period 2 (as in Table 11 above). ^(b)Data for AUC₀₋₂₄ andC_(max) from a 200 mg dose were normalized to a 225 mg dose. ^(c)Datafor AUC₀₋₂₄ and C_(max) from a 400 mg dose were normalized to a 225 mgdose.

Table 13 provides additional data that are corrected for carry-overeffect and includes all the data from both periods (i.e., samples fromentire Period 1 and Period 2).

TABLE 13* C_(max) AUC₀₋₂₄ AUC₀₋₁₂₀ AUC₀₋₁₆₈ AUC_(0-∞) Treatment PeriodSubject (ng/mL) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL)Fasted 1 3002 916 3648 4582 4864 5544 3003 431 3479 4757 5159 7399 3005806 4473 5940 6226 6841 3008 423 1725 2162 2279 2634 3009 530 2654 34173599 4099 3011 372 2107 2868 3014 3432 3013 556 2275 3064 3237 3604 3015425 2793 3660 3813 4180 Mean 557 2894 3806 4024 4717 CV % 36 32 32 32 36Fasted 2 3001 528 2186 2743 2916 5019 3004 685 3233 4219 4480 6296 3006563 2046 2867 3009 5161 3007 250 1876 2706 2922 6210 3010 473 2617 36123825 5854 3012 595 1808 2291 2438 4287 3014 719 2107 2769 2969 4110 3016576 2159 2993 3170 5254 Mean 549 2254 3025 3216 5274 CV % 26 21 20 20 16Fed 1 3001 608 3169 4091 4361 5298 3004 823 4363 5935 6313 7591 3006 3282876 3538 3740 4381 3007 915 3577 4968 5400 8572 3010 449 3949 5473 58206730 3012 613 2809 3562 3778 4419 3014 787 4160 5154 5371 5884 3016 5313524 4710 5067 6346 Mean 632 3553 4679 4981 6153 CV % 32 16 19 19 24 Fed2 3002 649 4450 5887 6278 10031 3003 519 3381 4691 5239 11462 3005 10546737 8707 9139 14742 3008 591 2947 3984 4272 7282 3009 806 3857 51165451 8667 3011 882 4716 5994 6236 8157 3013 570 3102 4528 4916 7244 3015920 5605 6819 7126 10551 Mean 749 4349 5716 6082 9767 CV % 26 30 27 2526 *Values were corrected for the carry-over effect.

Additional studies can be conducted to determine absolutebioavailability of a single dose of compound 1 in a SDD formulationusing a microdose of ¹⁴C-labeled compound 1 (free base).

Example 8 Manufacturing Process for Hot Melt Extrusion Formulations

Various hot melt extrusion (HME) formulations were prepared. Thepreferred polymers were found to be Kollidon® VA 64 (Copovidone),HPMCAS-MF (Hypromellose Acetate Succinate), and Kollidon® K30 (Povidone,PVP). Dissolution properties of these formulations are provided below inExample 9.

Briefly, the following process was developed to prepare an HMEformulation with 20% (w/w) compound 1 with HPMCAS-MF. Vitamin E TPGS waspre-milled to reduce particle size down to ≦600 micron, and compound 1was pre-sieved. Then, a pre-blend was prepared having 20% (w/w) sievedcompound 1, 75% (w/w) HPMCAS-MF, and 5% (w/w) milled vitamin E TPGS. Thepre-blend was processed using a co-rotating twin screw extruder havingthe following heating zone set points: 75° C., 110° C., 130° C., 140°C., and 95° C.; and the resultant extrudate was collected and processedfurther by milling (pelletizing) to reduce its particle size to ≦500microns. Approximately half of the milled/pelletized extrudate wassieved and blended with half of the microcrystalline cellulose. Then,various pharmaceutically acceptable excipients (i.e., lactose, sodiumlauryl sulphate, colloidal silicon dioxide, and croscarmellose sodium)were added and blended. The remaining milled/pelletized extrudate andmicrocrystalline cellulose were added and blended, where the resultantblend was co-milled and further processed by adding a lubricant (i.e.,magnesium stearate). Finally, the blend was used to fill hard gelatinshell capsules.

Each capsule contained 75 mg of compound 1 (free base) in a HPMCAS-MFand Vitamin E TPGS amorphous solid dispersion prepared by hot meltextrusion (HME). The quantitative composition of these HME capsules isshown in Table 14.

TABLE 14 Quantity per Component Function Standard Capsule (mg) Compound1 (free base) API C of A 75.00 Hypromellose acetate Polymer component ofPh. Eur., NF, JP 281.25 succinate Type MF the solid dispersion(HPMCAS-MF) Vitamin E TPGS (d-alpha Surfactant Ph. Eur., NF, JP 18.75tocopheryl polyethylene glycol 1000 succinate) Lactose monohydrateBinder-Filler Ph. Eur., NF, JP 74.74 Microcrystalline celluloseBinder-Filler Ph. Eur., NF, JP 74.74 Croscarmellose sodium DisintegrantPh. Eur., NF, JP 17.00 Sodium lauryl sulphate Wetting agent Ph. Eur.,NF, JP 4.24 Colloidal silicon dioxide Flow aid/Glidant NF 2.14 Magnesiumstearate Lubricant Ph. Eur., NF, JP 2.14 Capsule Shell, hard gelatinDosage form Na white opaque size 00 Total Fill Weight: 550.0Abbreviations: API = Active Pharmaceutical Ingredient; C ofA—Certificate of Analysis; Ph. Eur. = European Pharmacopoeia; NF =National Formulary; JP = Japanese Pharmacopeia

The formulation development materials were tested for dissolutionenhancement and for stability. The 1:4 ratio of API:polymer with a 5%surfactant was confirmed suitable. Solid-state characterization wasperformed on these formulations, including modulated dynamic scanningcalorimetry (mDSC) polarized light microscopy, kinetic solubility, andX-ray powder diffraction (XRRD), each to confirm that the API wasdispersed in an amorphous form.

Example 9 Dissolution Studies of Hot Melt Extrusion Formulations

Supersaturation dissolution kinetics provides valuable informationregarding the performance of different matrix polymers in combinationwith an active agent. In particular, such studies could provide insighton which formulations could provide enhanced bioavailability.Accordingly, dissolution studies were conducted on the following threeHME formulations: Kollidon® VA 64 (Copovidone), HPMCAS-MF (HypromelloseAcetate Succinate), and Kollidon® K30 (Povidone, PVP).

Briefly, the target concentration of the dissolution sample solution was1.1 mg/mL, or ten times the estimated sink dissolution sample solutionconcentration produced by a 100 mg dose when dissolved in 900 mL ofdissolution media. Triplicate preparations of about 10 mg of extrudate(2 mg of compound 1 in the three HME formulations) were transferred intoseparate micro-centrifuge tubes. About 1.8 mL of dissolution media waspreheated to 37° C. and added to each tube, where the tube was thenplaced into an incubator shaker at 37° C. and 250 rpm. Samples werecentrifuged at 13,000 rpm for one minute, and 25 μL aliquots of theclear supernatant were transferred into HPLC vials and diluted with 1.0mL of HPLC mobile phase (30%/70% of pH 6.6 buffer/acetonitrile) at 10′(minutes), 20′, 40′, 1 hr (hour), 1.5 hrs, 2 hrs, 4 hrs, and 24 hrs. Anisocratic HPLC method was applied for quantitation against a five pointcalibration curve in the range of 5.5-220 μg/mL (C18, 5 μm, 4.6×150 mmcolumn, and UV 216 nm detection). The HPLC sample solution targetconcentration was 27.1 μg/mL. Table 15 provides these data.

TABLE 15 Processing C_(max) AUC_(0-4 hr) Sample Conditions (μg/mL) SDT_(max) (mg * hr/mL) Control na 2.645 2.0 2 hours 0.008 (free base) 20%150° C., 178.6 15.8 20 minutes 0.483 compound 1/ no vacuum 80% 150° C.,150.5 21.1 40 minutes 0.445 Kollidon ® vacuum VA64 140° C., 116.5 8.1 40minutes 0.309 (Copovidone) no vacuum 20% 150° C., 115.2 62.1 40 minutes0.203 compound 1/ no vacuum Kollidon ® 150° C., 32.8 1.2 20 minutes0.092 K30 vacuum (Povidone) 140° C., 101.0 13.5 40 minutes 0.137 novacuum 20% 150° C., 691.8 22.5 4 hours 1.68 compound 1/ no vacuum 80%150° C., 647.4 26.2 4 hours 1.63 HPMCAS-MF vacuum 140° C., 661.6 29.0 4hours 1.66 no vacuum

As shown in Table 15, HPMCAS-MF (20% (w/w) compound 1) outperformed theother two polymers (copovidone or PVP) with a C_(max) of 647-692 μg/mL.All the tested formulations provided enhanced C_(max) values, ascompared to the Control (free base, compound 1).

Example 10 Phase I (Group 1) Study in Healthy Human Subjects toDetermine the Pharmacokinetics and Bioavailability of Compound 1Following Treatment with the HME Formulation Under Fasted or FedConditions

Bioavailability of the ion channel modulator compound 1 was studied inhealthy human subjects using the HME formulation, with subjects ineither a fed or a fasted state. The effect of food on bioavailabilityfrom a single oral dose of the HME formulation was thereby evaluated.Safety and tolerability of compound 1 were also evaluated.

This study utilized a single-center, single-dose open-label, 2-group,2-period randomized crossover design to address bioavailability underfasted and fed conditions. A total of 16 subjects were selected for thestudy. Inclusion criteria required men and women between 18 and 55 yearsof age, inclusive, with BMI between 18.0 and 30.0 kg/m2, inclusive, witha body weight not less than 50.0 kg, utilizing a reliable method ofcontraception, and that had signed an informed consent document.Subjects were screened for eligibility by safety and clinicalassessments, including informed consent, medical history, medicationhistory, demongraphics, physical examination, height, weight, BMI, serumpregnancy, clinical laboratory, HIV, Hepatitis B, Hepatitis C, vitalsigns, 12-lead ECG, urine drug screen, breath alcohol, concomitantmedications, haematology, and adverse event monitoring. Subjects wereexcluded on the basis of clinically significant pulmonary history,medical conditions that potentially alter drug metabolism, malignancywithin the previous 5 years, clinically significant allergies, creatineclearance, HIV, hepatitis B, hepatitis C, substance abuse, plannedsurgery during the course of the study, smoking, alcohol abuse, donationor loss of whole blood, caffeine consumption, experimental drug use,experimental medical device use, breast-feeding, use of non-prescriptionmedication, use of prescription medication, use of natural healthproducts, sodium intake, fluid intake, calcium intake, phosphorousintake, monoamine oxidase inhibitors, tricyclic antidepressants, febrileillness, abnormal body temperature, inability to swallow large capsules,inability to perform study requirements, employment by the principleinvestigator, inadequate venous access, and other exclusion criteria.Subjects were treated with an oral dose of 225 mg compound 1 as a hotmelt extrusion (225 mg HME) formulation, administered in a 75 mg APIdosage form as described in Example 8, Table 14. Dose was administeredwith approximately 8 fluid ounces of water to subjects in either a fed(high-fat meal) or a fasted state. Subjects were randomized between fedand fasted states during period 1 of the trial in equal numbers, and,following a washout period, assigned to the opposite state during period2. The fed condition is defined as the state of a subject following anovernight fast of at least 10 hours with a test meal provided 30 minutesprior to administration of the study drug. The subject must completelyconsume their respective meal before being dosed. Meals werestandardized high-fat meals and served according to a pre-determinedschedule throughout the inpatient portion of the study. The time of foodintake before and after study drug administration was documented. Thestandardized FDA-recommended high-fat meal will derive approximately 50%of total caloric content of the meal from fat with approximately 150,250, and 500 to 600 calories derived from protein, carbohydrate, andfat, respectively (total of approximately 900 to 1000 calories). Anexample test meal would include two eggs fried in butter, two strips ofbacon, two slices of white toast with butter and jam, 4 ounces of hashbrown potatoes, and 8 ounces of whole milk. The fasted condition isdefined as the state of a subject following an overnight fast of atleast 10 hours prior to the administration of the study drug without ameal prior to drug administration. Following drug administration,subjects were not allowed food for at least 4 hours. Water was allowedas desired except for one hour before and after drug administration.Outside of these restrictions, subjects in both fed and fastedconditions were provided fluid intake according to the subject'sindividual needs, with documentation. Fasted and fed groups were dosedand evaluated simultaneously.

Treatments of 225 mg HME were administered on day 1 of period 1 of thetrial, and subjects were admitted to the clinical research unit (CRU)for four days of inpatient evaluation. Subjects were discharged from theCRU upon completion of assessments on day 4, and reported to the CRU foradditional pharmacokinetic blood sampling and safety assessment on days5 and 6, completing period 1. There was a 7-day washout between thefirst and second period drug administrations. In the second period,subjects in a fed (high-fat meal) or fasted state were treated with anoral dose of 225 mg HME. The treatment was administered on day 1 ofperiod 2 of the trial, and subjects were admitted to the CRU. Subjectswere discharged from the CRU upon completion of assessments on day 4,and reported to the CRU for additional and follow-up pharmacokineticblood sampling and safety assessment on days 5, 6, 8, 15, 22, 29, and 36of period 2.

Pharmacokinetic assessments conducted during each treatment period wereperformed by the collection of venous blood samples via indwellingcatheter or direct venipuncture. The plasma concentration of the drugwas determined for each sample using a validated liquid chromatographycoupled with tandem mass (LC/MS/MS) assay, with a lower limit ofquantitation (LLOQ) of 0.1 ng/mL. The pharmacokinetic properties of thedrug were measured by the parameters listed in Table 16. Descriptivestatistics were calculated for these parameters and tabulated by feedingregimen and period. Safety of the trial subjects was assessed by thefollowing endpoints: adverse events, vital signs, ECG parameters,laboratory parameters, medical history and physical examination.

Table 17 displays AUC_(0-∞), AUC₀₋₂₄, and C_(max) values from bothperiods for all subjects, each subject having been cumulatively treatedunder both fasted and fed conditions. Mean, median, CV %, and geometricmean are calculated for each parameter as measured under fasted and fedconditions. The ratio of the fasted to the fed value of each parameteris shown for each subject and for summary statistics. The time to reachmaximum concentration, t_(max) is shown in Table 18 for fasted and fedconditions, as well as the difference between t_(max) fasted and t_(max)fed (fed minus fasted). Mean, median, CV %, and geometric mean arecalculated for fasted and fed conditions. In Table 19, half-life valuesof the drug are provided for all subjects in period 1 and period 2; theratio between the two and summary statistics are calculated. Table 20presents geometric mean AUC_(0-∞), AUC₀₋₂₄, and C_(max) values for bothHME and SDD formulations under fasted and fed conditions, as well as theratio of the fasted to fed values of the geometric mean for eachparameter.

TABLE 16 Parameter Description C_(max) The peak drug concentration,obtained directly from the data without interpolation. t_(max) Time tomaximum plasma concentration. t_(1/2) The terminal eliminationhalf-life, derived from the terminal portion of the plasma concentrationversus time curve. AUC_(0 t) Area under the plasma concentration versustime curve computed up to the last measurable concentration, where timeis post-dose. AUC₀₋₂₄ Area under the plasma concentration versus timecurve computed up to 24 hours postdose. AUC₀₋₁₂₀ Area under the plasmaconcentration versus time curve computed up to 120 hours postdose.AUC₀₋₁₆₈ Area under the plasma concentration versus time curve computedup to 168 hours postdose. AUC_(0-∞) Area under the plasma concentrationversus time curve, from time of dosing to infinity. AUC_(extrap)Percentage of the area extrapolated beyond the last quantifiable plasmaconcentration. λ_(z) Terminal first-order elimination rate constant.Cl/F Apparent plasma clearance after oral administration. V_(Z)/FApparent volume of distribution after oral administration. t_(lag) Thetime prior to the first measurable (non zero) concentration.

TABLE 17 AUC_(0-∞) AUC₀₋₂₄ C_(max) (hr * ng/mL) (hr * ng/mL) (ng/mL)Fasted Fasted Fasted Subject Fasted Fed Fed Fasted Fed Fed Fasted FedFed 1003 6039 6406 94% 3423 3753 91% 630 544 116% 1006 5443 6532 83%3422 3747 91% 621 399 156% 1007 6651 10547 63% 4310 5794 74% 804 813 99%1008 7579 8510 89% 3880 4811 81% 811 833 97% 1009 7199 11878 61% 35574877 73% 757 649 117% 1012 7809 14463 54% 4687 6947 67% 780 592 132%1013 5240 7619 69% 3452 5147 67% 712 1210 59% 1014 7257 7744 94% 43794583 96% 830 611 136% 1018 8262 6122 1180 1021 8180 4396 850 1022 77819441 82% 3806 3781 101% 917 397 231% 1024 4023 7386 54% 2679 4161 64%417 921 45% 1025 9487 7625 124% 3466 4361 79% 688 696 99% 1026 3372 642852% 1959 4486 44% 487 751 65% 1027 6497 15124 43% 4432 8684 51% 583 132744% 1028 3472 5870 59% 1933 2819 69% 294 628 47% Mean 6402 8922 73% 35854938 75% 679 770 103% Median 6651 7744 66% 3557 4583 74% 712 696 99% CV% 28% 32% 31% 24% 30% 22% 26% 37% 50% Geometric 6134 8550 70% 3472 475773% 653 724 92% Mean

TABLE 18 t_(max) (hr) Subject Fasted Fed Fed − Fasted 1003 2 6 4 10062.5 10 7.5 1007 3 8 5 1008 4 8 4 1009 3 6 3 1012 3 5 2 1013 2.5 5 2.51014 5 6 1 1018 6 1021 5 1022 3 5 2 1024 5 8 3 1025 4 6 2 1026 2.5 6 3.51027 6 5 −1 1028 5 5 0 Mean 3.7 6.3 2.8 Median 3 6 2.8 CV % 33% 24% 77%Geometric 3.5 6.2 Mean

TABLE 19 Half-Life (hr) Subject Period 1 Period 2 Ratio 1003 88 97 91%1006 191 125 153%  1007 49 129 38% 1008 95 92 103%  1009 103 130 79%1012 70 129 54% 1013 91 87 105%  1014 161 175 92% 1018 39 1021 89 1022303 73 415%  1024 37 193 19% 1025 91 552 16% 1026 64 89 72% 1027 39 12431% 1028 99 298 33% Mean 101 164 93% CV % 68 77 101% 

TABLE 20 AUC_(0-∞) AUC₀₋₂₄ C_(max) (hr * ng/mL) (hr * ng/mL) (ng/mL)Fasted Fasted Fasted Form. Subject Fasted Fed Fed Fasted Fed Fed FastedFed Fed HME Geometric 6134 8550 70% 3472 4757 73% 653 724 92% Mean CV %28% 32% 31% 24% 30% 22% 26% 37% 50% SDD Geometric 4279 6560 65% 24813837 65% 529 662 80% Mean CV % 29% 24% 18% 31% 27% 22% 30% 29% 41%

Example 11 Phase I (Group 2) Study in Healthy Human Subjects toDetermine the Pharmacokinetics and Bioavailability of Compound 1Following Treatment with the HME or SDD Formulations Under FedConditions

Bioavailability of the ion channel modulator compound 1 was studied inhealthy human subjects using SDD and HME formulations, with subjects ina fed state. The effect the SDD or HME formulation on bioavailabilityfollowing a single oral dose under fed conditions was thereby evaluatedand compared. Safety and tolerability of compound 1 was also evaluated.

This study utilized a single-center, single-dose open-label, 2-group,2-period randomized crossover design to determine bioavailabilityfollowing treatment with the SDD or HME formulation under fedconditions. A total of 16 subjects were selected by the criteriadescribed in Example 10.

Subjects were treated with an oral dose of 225 mg HME (as described inExample 8, Table 14) or 225 mg SDD (as described in Example 7) withapproximately 8 fluid ounces of water in the fed (standard meal) state.Subjects were randomized between HME and SDD formulations in equalnumbers during period 1 of the trial, and, following a washout period,assigned to the opposite formulation during period 2. The fed conditionis defined as the state of a subject following an overnight fast of atleast 10 hours with a test meal provided 30 minutes prior toadministration of the study drug. The subject must completely consumetheir respective meal before being dosed. Meals were standardized andstandard meals were served according to a pre-determined schedulethroughout the inpatient portion of the study. A standardized mealderived approximately 35% of total caloric content of the meal from fat,approximately 15-20% from protein, and approximately 45-50% fromcarbohydrates, with a total caloric content of approximately 400-450calories. An example test meal would have included ⅝ ounces Cheerios®, 1egg, 1 strip of bacon, 1 slice of toast with margarine, 6 ounces of lowfat milk, and 4 ounces of orange juice. The time of food intake beforeand after study drug administration was documented. Water was allowed asdesired except for one hour before and after drug administration.Outside of these restrictions, subjects in both fed and fastedconditions were provided fluid intake according to the subject'sindividual needs, with documentation. HME and SDD groups were dosed andevaluated simultaneously.

Treatments of 225 mg HME or SDD were administered on day 1 of period 1of the trial and subjects were admitted to the clinical research unit(CRU) for four days of inpatient evaluation. Subjects were dischargedfrom the CRU upon completion of assessments on day 4, and reported tothe CRU for additional pharmacokinetic blood sampling and safetyassessment on days 5 and 6, completing period 1. There was a 7-daywashout between the first and second period drug administrations. In thesecond period, subjects were treated with an oral dose of 225 mg HME or225 mg SDD in the fed (standard meal) state. The treatment wasadministered on day 1 of period 2 of the trial and subjects wereadmitted to the clinical research unit (CRU). Subjects were dischargedfrom the CRU upon completion of assessments on day 4, and reported tothe CRU for additional and followup pharmacokinetic blood sampling andsafety assessment on days 5, 6, 8, 15, 22, 29, and 36 of period 2.

Pharmacokinetic assessments conducted during each treatment period wereperformed by the collection of venous blood samples via indwellingcatheter or direct venipuncture. The plasma concentrations of the drugwas determined for each sample. Concentration of the drug was determinedusing a validated liquid chromatography coupled with tandem mass(LC/MS/MS) assay, with a lower limit of quantitation (LLOQ) of 0.1ng/mL. The pharmacokinetic properties of the drug were measured by theparameters listed in Table 16. Descriptive statistics were calculatedfor these parameters and tabulated by formulation and period. Safety ofthe trial subjects was assessed by the following endpoints: adverseevents, vital signs, ECG parameters, laboratory parameters, medicalhistory, and physical examination.

In Table 21, the mean AUC_(0-∞), mean AUC₀₋₂₄, and mean C_(max) valuesfrom both periods for all subjects, each subject having beencumulatively treated with both HME and SDD formulations. Mean, median,CV %, and geometric mean are calculated for each parameter as measuredfollowing treatment with the HME or SDD formulation. The ratio of theHME and SDD value for each parameter is shown for each subject and forsummary statistics. FIG. 12 displays box plot representations ofAUC_(0-∞) data for the HME formulation under fasted and fed conditions(as in Example 10), as well as AUC_(0-∞) data for HME and SDDformulations under fed conditions (as in this Example). FIG. 13 displaysbox plot representations of C_(max) data for the HME formulation underfasted and fed conditions (as in Example 10), as well as C_(max) datafor HME and SDD formulations under fed conditions (as in this Example).

The time to reach maximum concentration, t_(max), is shown in Table 22for all HME and SDD samples, as well as the difference between t_(max)HME and t_(max) SDD (fed minus fasted). Mean, median, CV %, andgeometric mean are calculated for the HME and SDD formulations. Theeffect of period on terminal half-life is displayed in Table 23, whichshows the half-life value of each subject in each period; the ratiobetween the two and summary statistics are calculated.

TABLE 21 AUC_(0-∞) AUC₀₋₂₄ C_(max) (hr * ng/mL) (hr * ng/mL) (ng/mL) HMEHME HME Subject HME SDD SDD HME SDD SDD HME SDD SDD 1001 12161 10620115% 6033 6591 92% 1242 1470 84% 1002 9824 7188 137% 6492 4484 145% 1450894 162% 1004 9922 12851 77% 6198 7150 87% 1730 1302 133% 1005 6415 5405119% 3589 3672 98% 915 904 101% 1010 6627 5450 122% 4028 3967 102% 862788 109% 1011 23084 6840 1420 1015 6932 8153 85% 4561 4969 92% 467 85854% 1016 4863 5940 82% 3220 3447 93% 765 873 88% 1017 7865 7287 108%4188 5094 82% 909 1040 87% 1019 10983 10317 106% 5276 6208 85% 1124 157072% 1020 5603 5771 97% 3376 3440 98% 442 873 51% 1023 5884 5899 100%3770 3746 101% 697 901 77% 1029 7615 7935 96% 4284 4243 101% 772 908 85%1030 8878 9163 97% 5879 5200 113% 1470 1122 131% 1031 6897 6241 111%4492 4263 105% 1365 967 141% 1032 10377 7568 137% 3282 3292 100% 909 811112% Mean 8056 8680 93% 4578 4788 100% 1008 1044 99% Median 7615 7427106% 4284 4373 98% 909 906 88% CV % 27 51 17% 25 27 15% 37 24 32%Geometric 7786 8004 97% 4454 4636 99% 939 1018 94% Mean

TABLE 22 t_(max) (hr) HME Subject HME SDD SDD 1001 5 3 167% 1002 3 3100% 1004 5 3 167% 1005 5 5 100% 1010 4 3 133% 1011 5 1015 10 5 200%1016 5 5 100% 1017 5 3 167% 1019 5 5 100% 1020 5 5 100% 1023 5 3 167%1029 5 5 100% 1030 5 4 125% 1031 5 5 100% 1032 5 5 100% Mean 5 4 128%Median 5 5 100% CV % 28 23  28% Geometric 5 4.1 124% Mean

TABLE 23 Half-Life (hr) Subject Period 1 Period 2 Ratio 1001 96 193 50%1002 114 98 116%  1004 72 71 101%  1005 105 116 91% 1010 77 114 68% 1011617 1015 79 104 76% 1016 75 171 44% 1017 75 176 43% 1019 270 417 65%1020 73 82 89% 1023 115 106 108%  1029 112 149 75% 1030 92 155 59% 103194 137 69% 1032 163 400 41% Mean 139 166 73% CV % 98 63 33%

Other Embodiments

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure come within known or customary practice within theart to which the invention pertains and may be applied to the essentialfeatures hereinbefore set forth.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

1. A pharmaceutical composition in unit dosage form for oral administration comprising a solid dispersion of from about 20 mg to about 250 mg of substantially amorphous compound 1 in a matrix polymer, wherein the percentage loading of said compound 1 in said solid dispersion is from about 10% to about 80% (w/w).
 2. The pharmaceutical composition of claim 1, wherein the percentage loading of said compound 1 in said solid dispersion is from about 10% to about 50% (w/w).
 3. The pharmaceutical composition of claim 1, wherein said unit dosage form comprises from about 70 mg to about 250 mg of compound
 1. 4. A method to treat pain in a subject in need thereof, said method comprising administering to said subject an effective amount of the pharmaceutical composition of claim
 1. 